Critical appraisal on REN(Remote Electrical Neuromodulation) by Dr Reddy's-Digital Therapeutics

[06/05, 8:42 am] Dr Rakesh Biswas: We were recently discussing one of our migraine patient's journey record and clinical events monitoring and we became aware of this tech marketed by Dr Reddy's :

Question is: does Dr Reddy's hold a patent on Remote Electrical Neuromodulation (REN)?

It does supplement the tech with other biofeedback as well as patient event headache journey monitoring tech although it's key feature is REN. 

Question 2:

What's the scientific evidence of REN in terms of efficacy (preferably in a PICO format)? 

News clip that stimulated the above two answer finding journeys:

https://timesofindia.indiatimes.com/gadgets-news/dr-reddys-nerivio-device-review-smart-pain-relief/articleshow/107822357.cms
[06/05, 1:00 pm] Hemanth AI Pune: There are multiple research paper in this showcasing thier finding
[06/05, 1:04 pm] Hemanth AI Pune: Theranica Enters Into Agreement With Dr. Reddy's for Commercializing Nerivio® in India
[06/05, 1:06 pm] Hemanth AI Pune: So the base technology is Remote electrical neuromodulation and the product using this tech called Nerivio is build by theranica and now they commercialising it in Indian in collaboration with Dr Reddy
[06/05, 4:20 pm] Dr Rakesh Biswas: But does theranica have a patent on the base technology of REN or it hasn't been patented at all?
[06/05, 4:22 pm] Dr Rakesh Biswas: Please share a link to the full paper. We need to know the details of the claimed results particularly how they evaluated the pain and it's relief and how they blinded the evaluators
[06/05, 4:24 pm] Hemanth AI Pune: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519197/
[06/05, 4:29 pm] Dr Rakesh Biswas: The title itself suggests that there was no blinding. How did they take into account evaluator as well as patient participant bias because if the patient and evaluators know they have been given the intervention they would automatically feel it's the effect of the intervention?
[06/05, 4:32 pm] Hemanth AI Pune: Correct , but this was regarding REN and there many such published paper for other conditions as well
[06/05, 4:32 pm] Dr.Dinesh Datta: Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial

https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14469
[06/05, 4:34 pm] Dr Rakesh Biswas: This looks promising! 

Please share the data in the pico format
[06/05, 4:36 pm] Dr.Dinesh Datta: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval −3.9 to −1.5], p < 0.001). The significance was maintained when analyzing the episodic (−3.2 ± 3.4 vs. −1.0 ± 3.6, p = 0.003) and chronic (−4.7 ± 4.4 vs. −1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group
[06/05, 4:40 pm] Dr.Dinesh Datta: Population (P):
  - Adults diagnosed with migraine, including both episodic and chronic migraine sufferers.
  - Total participants randomized: 248 (128 in REN group, 120 in placebo group)
  - Participants included in modified intention-to-treat (mITT) analysis: 179 (95 in REN group, 84 in placebo group)

Intervention (I):
  - REN stimulation intervention administered every other day for 8 weeks.
  - Baseline observation phase: 4 weeks

Comparison (C):
  - Placebo stimulation administered every other day for 8 weeks.
  - Baseline observation phase: 4 week

Outcomes (O):
  1. Primary Outcome:
     - Reduction in mean number of migraine days per month from baseline:
       - REN group: Mean reduction of 4.0 days (SD of 4.0 days)
       - Placebo group: Mean reduction of 1.3 days (SD of 4.0 days)
       - Therapeutic gain: 2.7 days (95% confidence interval −3.9 to −1.5), p < 0.001

  2. Secondary Outcomes:
     - Reduction in moderate/severe headache days:
       - REN group: Mean reduction of 3.8 days (SD of 3.9 days)
       - Placebo group: Mean reduction of 2.2 days (SD of 3.6 days)
       - p = 0.005
     - Reduction in headache days of all severities:
       - REN group: Mean reduction of 4.5 days (SD of 4.1 days)
       - Placebo group: Mean reduction of 1.8 days (SD of 4.6 days)
       - p < 0.001
     - Percentage of patients achieving 50% reduction in moderate/severe headache days:
       - REN group: 51.6% (49 out of 95 participants)
       - Placebo group: 35.7% (30 out of 84 participants)
       - p = 0.033
     - Reduction in days of acute medication intake:
       - REN group: Mean reduction of 3.5 days (SD of 4.1 days)
       - Placebo group: Mean reduction of 1.4 days (SD of 4.3 days)
       - p = 0.001

 Safety Outcome:
     - Incidence of serious device-related adverse events: No serious device-related adverse events reported in either group.
[06/05, 4:44 pm] Dr.Dinesh Datta: This study appears to be well designed and conducted.
Sample size is decent?
More details on baseline characteristics would be preferable.Double blinded and multicentered,implies good generalisability..
[06/05, 4:48 pm] Dr Rakesh Biswas: How did they blind the participants?
[06/05, 4:48 pm] Dr.Dinesh Datta: Of the mITT dataset, 43.2% (41/95) of the participants in the REN group and 34.5% (29/84) of the placebo made a correct guess, while most participants in both groups made a wrong guess, did not know, or did not answer. The difference between the correct guesses in the two groups was analyzed using a 2 × 2 chi-square test, indicating lack of statistically significant difference (p = 0.237).

A similar analysis was done on the ITT dataset, in which 39.1% (50/128) of the REN and 30.8% (37/120) of the placebo group participants correctly guessed their device, without a statistically significant difference (p = 0.175).
[06/05, 4:48 pm] Dr.Dinesh Datta: miTT-modified intent to treat
[06/05, 4:48 pm] Dr.Dinesh Datta: That's what I was looking at
[06/05, 4:49 pm] Dr Rakesh Biswas: Every other day intervention? What happened on the other days?
[06/05, 4:51 pm] Dr.Dinesh Datta: With respect to limitations of the study, the subanalyses differentiating between participants who took additional preventive medications and those who did not are based on a partial, smaller sample size of those who took preventive medications. Moreover, medical history regarding failure on previous preventive medications was not collected during the study, yet half of the participants who took an additional preventive medication took second-line preventives, suggesting that first-line preventives had failed in the past. Thus, for a more profound assessment of the different responses among users of different preventive drugs, as well as history of preventive failures, a designated study may be required. Another limitation is that the definition of a migraine day included a possible combination of headache and aura, which is not in accordance with IHS guidelines;38 however, no such instances were recorded, and thus this has no bearing on the study's results. Last, the study's inclusion criteria allowed for a single preventive agent, potentially limiting generalizability of the results in those taking two or more preventives.

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