Govt releases expert consensus statement on ICU admission and discharge criteria

For the first time, the Union Ministry of Health and Family Welfare has released an Expert Consensus Statement defining patients’ admission and discharge criteria to the Intensive Care Unit (ICU) and other related details.

These guidelines for Intensive Care Unit Admission and Discharge Criteria, compiled by a total number of 24 experts and released by the Directorate General of Health Services (DGHS) operative under the Union Health Ministry, addressed several issues including ICU Admission criteria and specifically it defined the critically ill patients who should not be admitted to the ICU.

For more details, check out the link given below:

GOI Releases Expert Consensus Statement On ICU Admission And Discharge Criteria, Key Takeaways

Powered by WPeMatico

Pfizer gene therapy for bleeding disorder approved in Canada

Canada: Pfizer said on Wednesday that Canada’s health regulator approved its gene therapy for the treatment of a rare inherited bleeding disorder called hemophilia B ahead of a U.S. decision.

The approval was based on late-stage trials that showed a single dose of the therapy, to be sold under the brand name Beqvez, was superior to the current standard of care which involves replacing a blood-clotting protein called factor IX.

The U.S. Food and Drug Administration (FDA) had in November 2022 approved CSL’s Hemgenix, making it the first one-time gene therapy for hemophilia B.

CSL had acquired exclusive global rights to Hemgenix from uniQure NV in 2021.

Pfizer is also seeking U.S. approval for its experimental antibody, marstacimab, to treat hemophilia A and B.

Hemophilia B is found in 1 in 40,000 people and represents about 15% of patients with hemophilia, according to the FDA.

The U.S. health regulator is expected to give its decision on Pfizer’s therapy in the second quarter of 2024.

Read also: CDSCO panel Approves Pfizer’s Protocol Amendment Proposal for Anti-cancer Drug Elranatamab

Powered by WPeMatico

Dr RV Asokan takes charge as National president of Indian Medical Association

Kollam: On a momentous occasion at the 98th national conference of the Indian Medical Association (IMA) held at Kovalam, Dr R.V. Asokan, a distinguished doctor from Kerala, has officially assumed the position of national president of the Indian Medical Association (IMA). Dr Asokan is a practising general physician running a 43 bedded hospital, in Punalur, a small town in Kollam district of Kerala.

Dr. Asokan’s ascendancy to the prestigious position is a testament to his notable contributions and leadership within the medical fraternity. Post MBBS, he completed his MD in General Medicine. He was the IMA state secretary of Kerala state for 3 years and also served as its state president. Having previously served as the IMA national secretary and held key positions at both the state chapter as president and secretary, Dr Asokan brings a wealth of experience and expertise to his new role. His dedicated service at various levels within the IMA underscores a commitment to advancing healthcare initiatives and advocating for the medical community.

Also Read: Hospitals cannot admit critically ill patients in ICU without consent: GOI ICU Admission guidelines

He conceived and established IMAGE which was a project to handle bio-medical waste of the entire Kerala, he was the chairman of the scheme for six years. He also played the lead in bringing the Rs 100 crore GFATM TB public-private mix project to IMA and served as its National coordinator for 6 years. He served for two years in the Strategy and Technical Advisory Group for TB in WHO (Geneva) and is one of the contributors of international standards for TB care. He served as the National Joint Secretary of the IMA Hospital Board of India for 4 years and its chairman for the past 4 years. 

As per a recent media report by The Hindu, the esteemed vice-presidents of IMA accompanying Dr Asokan include Gunasekharan from Tamil Nadu, Shivkumar Utture from Maharashtra, Suresh Gutta from Telangana, and Ashok Sharda from Rajasthan. Anil Kumar Naik, representing Gujarat, has assumed the pivotal role of the national secretary general, overseeing crucial administrative functions. 

The team of joint secretaries includes Munish Prabhakar from Haryana, Prakash Lalchandani from Delhi, M. Venkatachalapathy from Karnataka, and Pradeep Kumar Nemani from West Bengal, contributing to the collaborative leadership structure of the IMA. Shitij Bali, hailing from Delhi, has taken on the role of finance secretary, overseeing the financial affairs of the association.

Powered by WPeMatico

GOI Releases Expert Consensus Statement on ICU Admission and Discharge Criteria, Key Takeaways

New Delhi: For the first time, the Union Ministry of Health and Family Welfare has released an Expert Consensus Statement defining patients’ admission and discharge criteria to the Intensive Care Unit (ICU) and other related details.

These guidelines for Intensive Care Unit Admission and Discharge Criteria, compiled by a total number of 24 experts and released by the Directorate General of Health Services (DGHS) operative under the Union Health Ministry, addressed several issues including ICU Admission criteria and specifically it defined the critically ill patients who should not be admitted to the ICU.

Apart from this, these guidelines also clarified the ICU Discharge criteria, further defining the minimum patients monitoring required while awaiting an ICU bed, the minimum stabilisation required before transferring a patient to ICU, and the minimum monitoring required for transferring a critically ill patient (inter-facility transfer to hospital/ICU).

Referring to the Expert Consensus Statements, the guidelines mentioned, “The Expert Consensus statements have been made using the Delphi methodology to generate consensus. The Steering Group for Delphi process was SNM, RKM and PN who conducted the Delphi surveys using Google forms, prepared the Delphi statements and the reports. The Steering Group did not vote in Delphi surveys. The rest of the Experts voted anonymously over three rounds. Consensus was defined as achieved for an option when voted by 70% or more of the Experts. Stability was checked for all responses. The final statements were drafted from the MCQ responses that achieved consensus and stability.”

Expert Consensus Statement- Seven Things to Remember:

1. First of all, these guidelines clarified that the “Criteria for admitting a patient to ICU should be based on organ failure and need for organ support or in anticipation of deterioration in the medical condition.” 

Other ICU-related details including admission, discharge, patient monitoring, and transfer of patients are as follows:

2. ICU Admission Criteria: 

The guidelines lay down the following admission criteria to the Intensive Care Unit:

 Altered level of consciousness of recent onset

 Hemodynamic instability (e.g., clinical features of shock, arrythmias)

 Need for respiratory support (e.g. escalating oxygen requirement, de–novo respiratory failure requiring non-invasive ventilation, invasive mechanical ventilation, etc.)

 Patients with severe acute (or acute–on–chronic) illness requiring intensive monitoring and/or organ support

 Any medical condition or disease with anticipation of deterioration

 Patients who have experienced any major intraoperative complication (e.g. cardiovascular or respiratory instability)

 Patients who have undergone major surgery, (e.g. thoracic, thoraco–abdominal, upper abdominal operations, trauma who require intensive monitoring or at a high risk of developing postoperative complications).

3. Patients who Should not be Admitted to the ICU:

Apart from clarifying the admission criteria for the ICUs, the new guidelines also clarified regarding the patients who cannot get admitted to the ICU. The details of patients who should not be admitted to ICU are as follows:

 Patient’s or next–of–kin informed refusal to be admitted in ICU

 Any disease with a treatment limitation plan

 Anyone with a living will or advanced directive against ICU care

 Terminally ill patients with a medical judgement of futility

 Low priority criteria in case of pandemic or disaster situation where there is resourcelimitation (e.g. bed, workforce, equipment).

4. ICU Discharge Criteria:

Along with the admission criteria, the Union Government has also specified the criteria for getting a discharge from the ICU. The following patients or the following situations can fulfill the ICU Discharge Criteria:

 Return of physiological aberrations to near normal or baseline status

 Reasonable resolution and stability of the acute illness that necessitated ICU admission

 Patient/family agrees for ICU discharge for a treatment-limiting decision or palliative care.

 Based on lack of benefit from aggressive care (should be a medical decision, not obligating family agreement and as far as possible should not be based on economic constraints).

 For infection control reasons with ensuring appropriate care of the given patient in a non ICU location

 Rationing (i.e., prioritisation in the face of a resource crunch). In this event there should be an explicit and transparent written rationing policy that should be fair, consistent and reasonable.

5. The Minimum patient monitoring required while awaiting an ICU bed: 

The Government has clearly mentioned in the guidelines regarding the minimum patient monitoring that is required while awaiting an ICU bed. These following factors should be monitored:

 Blood pressure (continuous/intermittent)

 Clinical monitoring (e.g., pulse rate, respiratory rate, breathing pattern, etc.)

 Heart rate (continuous/intermittent)

 Oxygen saturation – SpO2 (continuous/intermittent)

 Capillary refill time

 Urine Output (continuous/intermittent)

 Neurological status e.g. Glasgow Coma Scale (GCS), Alert Verbal Pain Unresponsive (AVPU) scale etc.

 Intermittent temperature monitoring

 Blood sugar

6. The Minimum stabilisation required before transferring a patient to ICU: 

As per the guidelines, the following aspects related to the stabilisation of a patient needs to be ensured before transferring a patient to the ICU:

 Ensuring a secure airway (i.e., tracheal intubation if the patient has a GCS ≤8)

 Ensuring adequate oxygenation and ventilation.

 Stable haemodynamics, either with or without vasoactive drug infusion.

 Ongoing correction of hyperglycemia/hypoglycemia and other life-threatening electrolyte/metabolic disturbances

 Initiation of definitive therapy for life-threatening condition (e.g., external fixation of a fractured limb, administration of antiepileptics for recurrent seizures, antiarrhythmic drug infusion for unstable arrhythmias etc, intravenous antibiotics for sepsis)

7. The Minimum monitoring required for transferring a critically ill patient (inter-facility transfer to hospital/ICU):

The guidelines also specified the minimum monitoring that is required to transfer a critically ill patient. As per the new guidelines, the following conditions should be monitored: 

 Blood pressure (continuous/intermittent)

 Clinical monitoring (pulse rate, respiratory rate, breathing pattern, etc.)

 Continuous Heart rate

 Continuous SpO2

 Neurological status (AVPU, GCS, etc.)

The Government guidelines for admission of patients to ICU have been issued more than 7 years after the Supreme Court took cognisance of the issue. Medical Dialogues had reported back in 2016 that taking into account the stream of medical negligence cases being filed against the medical professionals and hospital, the Supreme Court bench had asked the Central Government, and the erstwhile Medical Council of India (MCI), which has now been replaced by the National Medical Commission (NMC), to answer whether any guidelines are prescribed for private hospitals on providing care to patients in the Intensive Care Unit (ICU) and Critical Care Unit (CCU).

Also Read: Give guidelines on admission to ICU,CCU: SC to MCI, Centre

Powered by WPeMatico

Cow’s milk and donated breast milk equally effective and enriching in extremely preterm infants

Infants born extremely prematurely need to get enrichment as an addition to breast milk. But does it make any difference whether the enrichment is made from breast milk or cow’s milk when it comes to the risk of severe complications in children? This has been investigated by a large clinical study led from Linköping, Sweden.

Infants born extremely prematurely, between weeks 22 and 27 of pregnancy, are among the most vulnerable patients in healthcare. The risk of serious complications is very high. Almost one in four extremely premature babies die before the age of one.

There is strong research support for giving breast milk to these children rather than formula made from cow’s milk. It is known that cow’s milk-based formula increases their risk of getting, for example, severe intestinal inflammation and sepsis (severe blood-born infection).

“In Sweden, all extremely preterm infants receive breast milk from their mother or donated breast milk. Despite this, almost one in ten children get a severe inflammation of the intestine called necrotising enterocolitis. It’s one of the worst diseases you can have. At least three out of ten children die and those who survive often have neurological problems afterwards,” says Thomas Abrahamsson, professor at Linköping University and senior physician at the neonatal department at the University Hospital in Linköping, who led the current study.

Historically, there have been very few studies on extremely preterm infants where treatments have been compared against each other. Therefore, there is a great need for clinical studies that can provide scientific support for how these children should be treated to have better chances of survival and a good life.

In some countries, such as Sweden, infants are fed exclusively with either their mother’s breast milk or donated breast milk. However, in order for extremely preterm infants to grow as well as possible, they need more nutrition than breast milk contains. This is why breast milk is supplemented with extra protein, so-called enrichment.

The enrichment has previously been made from cow’s milk. But there have been suspicions that cow’s milk-based enrichment increases the risk of severe complications. Today, there is enrichment that is based on donated breast milk, and which has begun to be used in healthcare in some places. The big question is whether it can reduce the risk of diseases in extremely preterm infants.

The current study, called N-Forte (the Nordic study on human milk fortification in extremely preterm infants), is the largest that has been carried out to seek answers to this question. The results have been eagerly awaited by paediatricians and others caring for these fragile infants.

“We concluded that it doesn’t matter whether extremely preterm infants get enrichment made from cow’s milk or made from donated breast milk,” says Thomas Abrahamsson.

Although the study indicates that there was no difference between the two options, its results can be useful. The breast milk-based product is estimated to cost more than SEK 100,000 per child, which would be equivalent to around SEK 40 million if the product were to be used in Swedish healthcare.

“On the one hand, we’re disappointed that we didn’t find a positive effect of enrichment based on breast milk. On the other hand, it’s a large and well-done study and we can now say with great certainty that it doesn’t have an effect in this patient group. This is also important knowledge, so that we don’t invest in expensive products that don’t have the desired effect,” says Thomas Abrahamsson.

The N-Forte study included 228 extremely preterm infants, randomly divided into two equally-sized groups that received enrichment made from breast milk and cow’s milk respectively. The researchers examined whether the two groups differed in the incidence of necrotising enterocolitis, sepsis and death. Of the children treated with breast milk-based enrichment, 35.7% had these complications, while the corresponding proportion was 34.5% in the group receiving cow’s milk-based enrichment, which means that there was no difference betEClinicalMedicineween the groups.

The results of the study are in line with a smaller study from Canada published in 2018. In that study, the researchers also did not see any difference between the two types of enrichment on necrotising enterocolitis and severe sepsis.

The study was conducted at 24 neonatal departments in Sweden, with financial support from the Swedish Research Council, the Swedish Research Council in Southeast Sweden (FORSS), ALF funds and the company Prolacta Bioscience.

Reference:

Georg Bach Jensen, Magnus Domellöf, Fredrik Ahlsson, Anders Elfvin, Lars Navér, Thomas Abrahamsson,Effect of human milk-based fortification in extremely preterm infants fed exclusively with breast milk: a randomised controlled trial, DOI:https://doi.org/10.1016/j.eclinm.2023.102375.

Powered by WPeMatico

Guselkumab tied with early improvement in psoriasis associated arthritis

Guselkumab associated with early improvement of joints and reduced progression of psoriatic arthritis suggests a new study published in the Clinical Rheumatology.

Assess relationship between earlier clinical improvement and radiographic progression (RP) over 2 years in guselkumab-treated patients with active psoriatic arthritis (PsA).

Post hoc analyses combined data from DISCOVER-2 biologic-naïve adults with active PsA randomized to either guselkumab 100 mg every 4 weeks (Q4W) or guselkumab at W0, W4, then Q8W. Correlations (Spearman’s coefficient) between baseline disease parameters and total PsA-modified van der Heijde-Sharp (vdH-S) score were examined. Repeated-measures mixed models, adjusted for known RP risk factors, assessed the relationship between Disease Activity Index in PsA (DAPSA) improvement, DAPSA improvement exceeding the median or the minimal clinically important difference (MCID), or DAPSA low disease activity (LDA) at W8 and RP rate, assessed by change from baseline in vdH-S score through W100.

Results

Baseline age, PsA duration, CRP level, and swollen joint count, but not psoriasis duration/severity, weakly correlated with baseline vdH-S score. Elevated baseline CRP (parameter estimate [β] = 0.17–0.18, p < 0.03) and vdH-S score (β = 0.02, p < 0.0001) significantly associated with greater RP through W100. Greater improvement in DAPSA (β = -0.03, p = 0.0096), achievement of DAPSA improvement > median (least squares mean [LSM] difference: -0.66, p = 0.0405) or > MCID (-0.67, p = 0.0610), or DAPSA LDA (-1.44, p = 0.0151) by W8 with guselkumab significantly associated with less RP through W100. The effect of W8 DAPSA LDA on future RP was strengthened over time among achievers vs. non-achievers (LSM difference enhanced from -1.05 [p = 0.0267] at W52 to -1.84 [p = 0.0154] at W100).

In guselkumab-treated patients with active PsA, earlier improvement in joint symptoms significantly associated with lower RP rates through 2 years, indicating blockade of the IL-23 pathway may modify long-term disease course and prevent further joint damage.

Reference:

Mease, P.J., Gottlieb, A.B., Ogdie, A. et al. Earlier clinical response predicts low rates of radiographic progression in biologic-naïve patients with active psoriatic arthritis receiving guselkumab treatment. Clin Rheumatol (2023). https://doi.org/10.1007/s10067-023-06745-y

Keywords:

Guselkumab, associated, early, improvement, joints, reduced, progression ,psoriatic,arthritis, Mease, P.J., Gottlieb, A.B., Ogdie, Clinical Rheumatology

Powered by WPeMatico

Bariatric surgery may improve left ventricular structure, function and strain

Bariatric surgery may improve left ventricular structure, function and strain suggests a new study published in the Journal of the American Heart Association.

Obesity leads to an increased risk of cardiovascular disease morbidity and death, including heart failure. Bariatric surgery has been proven to be the most effective long‐term weight management treatment. This study investigated the changes in cardiac structure and function after bariatric surgery, including left ventricular global longitudinal strain. 398 consecutive patients underwent bariatric surgery with pre‐ and postoperative transthoracic echocardiographic imaging at a US health system between 2004 and 2019. We compared cardiovascular risk factors and echocardiographic parameters between baseline and follow‐up at least 6 months postoperatively. Along with decreases in weight postoperatively, there were significant improvements in cardiovascular risk factors, including a reduction in systolic blood pressure levels from 132 mm Hg to 127 mm Hg, glycated haemoglobin levels from 6.5% to 5.7%, and low‐density lipoprotein levels from 97 mg/dL to 86 mg/dL. Left ventricular mass decreased from 205 g to 190 g, left ventricular ejection fraction increased from 58% to 60%, and left ventricular global longitudinal strain improved from −15.7% to −18.6% postoperatively. This study has shown the long‐term impact of bariatric surgery on cardiac structure and function, with reductions in left ventricular mass and improvement in left ventricular global longitudinal strain. These findings support the cardiovascular benefits of bariatric surgery.

Reference:

Impact of Bariatric Surgery on Left Ventricular Structure and Function. Diarmaid Hughes, Ali Aminian, Chao Tu, Yuichiro Okushi, Yoshihito Saijo, Rickesha Wilson, Nicholas Chan, Ashwin Kumar, Richard A. Grimm, Brian P. Griffin, W. H. Wilson Tang, Steven E. Nissen and Bo Xu. Originally published29 Dec 2023https://doi.org/10.1161/JAHA.123.031505Journal of the American Heart Association. 2024;13:e031505

Keywords:

Bariatric, surgery, may, improve, left, ventricular, structure, function, and strain, Journal of the American Heart Association, Diarmaid Hughes, Ali Aminian, Chao Tu, Yuichiro Okushi, Yoshihito Saijo, Rickesha Wilson, Nicholas Chan, Ashwin Kumar, Richard A. Grimm, Brian P. Griffin, W. H. Wilson Tang, Steven E. Nissen and Bo Xu.

Powered by WPeMatico

Lung Cancer Risk High in Never-Smokers With Positive Family History: Lancet

The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) has revealed compelling insights into the prevalence and risk factors of lung cancer among non-smokers. The findings were published in the Lancet Respiratory Medicine.

The study was conducted across 17 medical centers in Taiwan and primarily focused on individuals aged 55 to 75 years who never smoked or had minimal smoking history along with additional risk factors for lung cancer. Lung cancers in Taiwan are disproportionately affecting never-smokers with nearly 60% diagnosed at a very advanced stage.

The study spanned over 8 years and included 12,011 participants, of which 6009 had a family history of lung cancer. LDCT scans at baseline identified 17.4% as positive, leading to the diagnosis of lung cancer in 2.6% of participants. Also, 77.4% of diagnosed cases were at stage I which highlighted the potential impact of early detection.

Participants with a family history of lung cancer demonstrated a higher prevalence of invasive lung cancer with increasing age. Factors such as female sex and age over 60 correlated with an increased risk of lung cancer. Importantly, passive smoke exposure and cooking-related variables showed no significant associations with lung cancer. The LDCT screening exhibited a high sensitivity of 92.1% and specificity of 84.6% that emphasize its effectiveness in early detection.

This study also acknowledges the potential for overdiagnosis, specially in cases of adenocarcinoma in situ. Further investigations into risk factors for lung cancer in non-smokers, especially those without a family history will be important to refine the screening protocols and improving outcomes in this vulnerable population. 

Reference:

Chang, G.-C., Chiu, C.-H., Yu, C.-J., Chang, Y.-C., Chang, Y.-H., Hsu, K.-H., Wu, Y.-C., Chen, C.-Y., Hsu, H.-H., Wu, M.-T., Yang, C.-T., Chong, I.-W., Lin, Y.-C., Hsia, T.-C., Lin, M.-C., Su, W.-C., Lin, C.-B., Lee, K.-Y., Wei, Y.-F., … Yang, S.-C. (2023). Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study. In The Lancet Respiratory Medicine. Elsevier BV. https://doi.org/10.1016/s2213-2600(23)00338-7

Powered by WPeMatico

Goniotomy Viable Option for Glaucoma Patients with Previous Surgical Failure

A recent study has shed light on the promising role of goniotomy (GT) as a potential solution for individuals facing glaucoma recurrence after prior unsuccessful surgeries. The study was published in The Journal Of Glaucoma by Lin and colleagues. This innovative approach, evaluated through a prospective multicenter study, offers hope for improved outcomes and better management for this challenging condition.

Researchers conducted a comprehensive investigation on patients who underwent GT following one or multiple previous surgeries for glaucoma. The study aimed to assess the efficacy and safety of GT over 12 months, focusing on several critical outcome measures, including intraocular pressure (IOP) changes, visual acuity improvements, medication usage, and occurrence of adverse events.

  • Their findings, based on 38 eyes of 34 patients, revealed encouraging results. A significant proportion of eyes achieved success post-GT: complete success was observed in 42.1% of the eyes, meeting the criteria of a postoperative IOP within 6–18 mmHg with a 20% reduction from baseline, without the need for ocular hypotensive medications.

  • Additionally, 78.9% of the eyes attained qualified success, aligning with the criteria but allowing for postoperative medication use. Prior to the procedure, patients exhibited high baseline IOP levels, with a mean of 29.4±6.9 mmHg, which significantly decreased to 16.7±3.6 mmHg (a remarkable 43.2% reduction; P<0.001) by the 12-month mark post-surgery.

  • The median number of glaucoma medications used also saw a substantial decrease, from a preoperative median of 3.0 to 2.0 at month 12 (P<0.001).

  • While demonstrating promise, the study did note some associated complications post-GT, with common occurrences including hyphema (13.2%), IOP spike (7.9%), and corneal edema (5.2%). Notably, older age emerged as a contributing factor to surgical success.

This study’s conclusions strongly support the efficacy and safety of GT as a viable intervention for individuals facing recurrent glaucoma despite prior unsuccessful surgeries. The findings hold promise for patients seeking alternatives in managing this challenging condition

The insights gained from this research could significantly impact clinical practice, offering a potential solution for those with a history of unsuccessful glaucoma surgeries. The study encourages further exploration and adoption of GT, providing renewed hope for better outcomes in managing this complex ophthalmologic condition.

Reference:

Lin, F., Nie, X., Shi, J., Song, Y., Lv, A., Li, X., Lu, P., Zhang, H., Jin, L., Tang, G., Fan, S., Weinreb, R. N., & Zhang, X. Safety and efficacy of goniotomy following failed surgery for glaucoma. Journal of Glaucoma,2023;32(11):942–947. https://doi.org/10.1097/ijg.0000000000002301

Powered by WPeMatico

Treatment with cyclobenzaprine sublingual tablets may reduce pain in fibromyalgia patients

Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a biopharmaceutical company with marketed products and a pipeline of development candidates, today announced that the Phase 3 RESILIENT study evaluating TNX-102 SL (cyclobenzaprine HCl sublingual tablets) met its pre-specified primary endpoint in the second of two positive Phase 3 clinical trials, significantly reducing daily pain compared to placebo (p=0.00005) in participants with fibromyalgia (Table 1). Statistically significant and clinically meaningful results were also seen in all key secondary endpoints related to improving sleep quality, reducing fatigue, and improving overall fibromyalgia symptoms and function. Additionally, as it relates to improving daily pain, treatment with TNX-102 SL showed a robust and clinically meaningful analgesic effect size of 0.38, with rapid onset of action, separating from placebo for each week of the study. TNX-102 SL was well tolerated with an adverse event profile comparable to prior studies, and no new safety signals were observed. Tonix plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the second half of 2024 for TNX-102 SL for the management of fibromyalgia. An estimated 6 million to 12 million U.S. adults are living with fibromyalgia, the majority of whom are women.

TNX-102 SL is a tablet formulation containing 2.8 mg cyclobenzaprine HCl and is a novel, centrally-acting, non-opioid analgesic, designed to be taken once daily at bedtime for the management of fibromyalgia. RESILIENT was a 14-week randomized, double-blind, placebo-controlled trial of TNX-102 SL 5.6 mg, in which 457 participants with fibromyalgia were randomized in a 1:1 ratio to TNX-102 SL or placebo across 33 sites in the U.S. All participants received one 2.8 mg tablet of TNX-102 SL (2.8 mg) or placebo for the first 2 weeks, which was increased to two 2.8 mg tablets of TNX-102 SL (5.6 mg) or placebo for the remaining 12 weeks.

In December 2020, Tonix reported positive results from the first Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of fibromyalgia. The RELIEF study met its pre-specified primary endpoint, significantly reducing daily pain compared to placebo (p=0.010) in participants with fibromyalgia, and showing activity in key secondary endpoints.

“We believe that the positive results of RESILIENT and RELIEF show that fibromyalgia can be successfully treated by TNX-102 SL 5.6 mg and may provide the opportunity for Tonix to have the first FDA-approved drug for fibromyalgia in more than a decade,” said Seth Lederman, M.D., President and Chief Executive Officer of Tonix Pharmaceuticals. “We are now an important step closer to bringing a new, first-line treatment to fibromyalgia patients that offers broad symptom relief and favorable tolerability for chronic use and adherence. We believe that we are well positioned to submit an NDA to the FDA under the 505(b)(2) regulatory approval pathway in the second half of 2024, and are on track to supply the U.S. market upon FDA approval.”

Abbreviations: FIQ-R = Fibromyalgia Impact Questionnaire – Revised; NRS = Numeric Rating Scale; PROMIS = Patient-Reported Outcomes Measurement Information System

*Statistically significant; to control for overall type 1 error, a pre-specified, serial gatekeeping procedure was utilized.

1Analysis by mixed model repeated measures with multiple imputation unless otherwise indicated.

2Primary endpoint analysis for FDA approvals of Cymbalta® and Lyrica® in fibromyalgia.

3Pearson’s chi-squared test responder analysis, with missing data considered non-responders

“These data are terrific news for patients with fibromyalgia,” said Daniel J. Clauw, M.D., Professor of Anesthesiology, Medicine and Psychiatry at the University of Michigan. “Despite approved medications, there remains a need for new treatment options to better address the quality of life impacts many fibromyalgia patients experience on a chronic basis. TNX-102 SL is a non-opioid, centrally-acting analgesic, the active ingredient of which has a known, favorable safety profile from decades of use. The fact that cyclobenzaprine was also beneficial in many other key symptom domains, including sleep quality, sleep disturbance and fatigue, will be appreciated by fibromyalgia patients that struggle with not just pain but multiple other symptoms.”

“These positive data from RESILIENT and previously with RELIEF, with remarkable separation from placebo on pain, sleep, and fatigue, add support to TNX-102 SL’s proposed mechanism of improving sleep quality to improve the syndromal effects of fibromyalgia,” commented Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. “The sublingual formulation of TNX-102 SL, which uses our proprietary Protectic® and Angstro® technologies, is integral to our treatment paradigm. These technologies enable transmucosal delivery of cyclobenzaprine with distinctive pharmacokinetic properties that include rapid absorption after dosing and bypass of first-pass hepatic metabolism. I would like to thank the RESILIENT study participants and their families and caregivers, as well as the investigators and their hard-working staff who all made this a highly successful trial.”

Summary of Topline Results of the RESILIENT Study

The RESILIENT study achieved statistical significance on the pre-specified primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.8 [0.12] units) versus placebo (-1.2 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.7 [0.16] units, p=0.00005, Table 1). In addition, all pre-specified sensitivity analyses of the primary endpoint were statistically significant (p<0.001). Figure 1 shows reduction in pain across all weeks of the 14-week study, with nominal p<0.01 for every week. Note the rapid onset of action with separation from placebo at Week 1 was sustained throughout all weeks of dosing.

Abbreviations: LS = least squares; NRS = numerical rating scale; SE = standard error

The statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach, a 30 percent responder analysis, with 45.9% on active and 27.1% on placebo having a 30 percent or greater reduction in pain (Pearson Chi-Squared Test; difference in proportions [95% CI]: 18.8% [10.1%, 27.4%]; nominal p<0.001).

TNX-102 SL showed statistical significance (p≤0.001) on all six pre-specified key secondary efficacy outcome measures (Table 1).

Consistent with the proposed mechanism that TNX-102 SL acts in fibromyalgia through improving sleep quality, TNX-102 SL showed statistically significant improvement of sleep by two main measures. For the daily diary sleep quality ratings, improvement in sleep quality for TNX-102 SL (-1.8 [0.12] units) was significantly greater than that of placebo (-1.2 [0.12] units; LS mean [SE] difference from placebo: -0.6 [0.17] units; p<0.001). For the PROMIS Sleep Disturbance instrument, TNX-102 SL also demonstrated significantly greater improvement over placebo on T-scores (LS mean [SE] difference from placebo: -4.2 [0.79] units; p<0.001). Fatigue is another cardinal symptom of fibromyalgia and has a major impact on quality of life. TNX-102 SL showed significant improvement over placebo on the PROMIS Fatigue instrument T-scores (-3.0 [0.77] units; p<0.001).

The Fibromyalgia Impact Questionnaire – Revised (FIQ-R) is a 21-item self-rated instrument that assesses level of function, overall impact, and symptoms due to fibromyalgia, and the symptoms and function domains were key secondary endpoints in RESILENT. At Week 14 on the FIQ-R Symptoms domain, there was significantly greater improvement with TNX-102 SL than with placebo (LS mean [SE] difference from placebo: -7.7 [1.62], p<0.001). Similarly, TNX-102 SL resulted in greater improvement on FIQ-R Function (LS mean [SE] difference from placebo: -5.4 [1.66], p=0.001). Although not a key secondary efficacy endpoint, TNX-102 SL also separated from placebo on the FIQ-R Impact domain (nominal p=0.001). These results, along with the robust effects on improving sleep and fatigue, suggests broad symptomatic coverage of the syndrome of fibromyalgia.

Safety Results of the Phase 3 RESILIENT Study

In the RESILIENT study, TNX-102 SL was well tolerated and consistent with prior trials, with no new safety signals observed. Among participants randomized to the TNX-102 SL and placebo arms, 81.0% and 79.2%, respectively, completed the 14-week dosing period. As expected based on prior TNX-102 SL studies, administration site reactions were the most commonly reported adverse events and were higher in the TNX-102 SL treatment group (Table 2). Hypoaesthesia oral and paraesthesia oral, or tongue and mouth numbness or tingling, product taste abnormal (typically a bitter aftertaste upon dosing), and tongue discomfort were local effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in most occurrences. The only treatment-emergent adverse events that occurred at a rate of 3.0% or greater in either arm were these four oral adverse events, along with COVID-19, somnolence, and headache (Table 2). Adverse events resulted in premature study discontinuation in 6.1% of those who received TNX-102 SL compared with 3.5% of placebo recipients. There were a total of seven serious adverse events in five patients, five of which were experienced by three patients in the placebo arm, and two of which were in the TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was renal cancer, deemed unrelated to study drug, and the other was acute pancreatitis with onset 14 days after dosing was completed and reported as possibly related to study drug.

The Changes in Sexual Functioning Questionnaire short form (CSFQ-14) served as a safety measure for assessing potential adverse effects on sexual functioning. In females, the total score on the CSFQ-14 at Week 14 improved (indicating better sexual functioning) in the TNX-102 SL group compared with placebo (nominal p=0.010 by analysis of covariance). This potentially indicates an important tolerability advantage over pharmacotherapeutics which potently inhibit reuptake of serotonin. The low percentage of males in the safety population (<5%) did not allow meaningful analysis of the CSFQ-14 data.

About the Phase 3 RESILIENT Study

The RESILIENT study is a double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in the management of fibromyalgia. The two-arm trial randomized 457 participants in the U.S. across 33 sites. The first two weeks of treatment consist of a run-in period in which participants start on TNX-102 SL 2.8 mg (1 tablet) or placebo. Thereafter, all participants increase their dose to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12 weeks. The primary endpoint is the daily diary pain severity score change (TNX-102 SL 5.6 mg vs. placebo) from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation.

Powered by WPeMatico