Moderna has just announced that its RNA based vaccine is starting a phase 3 clinical trial with 30,000 subjects, so I thought it might be useful to take a look at the publicly available information about the trial, and how they got there. Let’s go logically and chronologically and start with the phase 1 safety study.
The Phase 1 study
A phase 1 study is a safety study. They usually have relatively few subjects, and different doses are given because dosing in terms of side effects is usually an important endpoint in a safety study.
Here is the “Brief Summary” of the Phase 1 study published by Moderna
This is a phase I, open-label, dose-ranging clinical trial in males and non-pregnant females, starting at 18 years of age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity, and immunogenicity of mRNA-1273 manufactured by ModernaTX, Inc. mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of SARS-CoV-2. Enrollment will occur at up to 3 domestic clinical research sites. One hundred and fifty-five subjects will be enrolled into one of thirteen cohorts (10 micrograms [mcg], 25 mcg, 50 mcg, 100 mcg, and 250 mcg). Subjects will receive an intramuscular (IM) injection (0.5 milliliters [mL]) of mRNA-1273 on Days 1 and 29 in the deltoid muscle and will be followed through 12 months post-second vaccination (Day 394). Follow-up visits will occur 1, 2, and 4 weeks post each vaccination (Days 8, 15, 29, 36, 43, and 57), as well as 3, 6, and 12 months post-second vaccination (Days 119, 209, and 394). The primary objective is to evaluate the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 5 dosages in healthy adults.”
Here is the study information from clinicaltrials.gov
I will be referring to other parts of it later on
The important parts of this summary are (IMO):
1. 155 subjects
2. All subjects have to be in good health, over 18 and not pregnant females
3. 2 shots of the vaccine, the second on day 29 (so 28 days from the first to the second shot)
4. There will be 13 different subgroups stratified by age group and vaccine dose.
5. Periodic follow up to assess response and report side effects for 13 months following the initial vaccine shot.
From the Study Design section, we learn the following:
Actual Enrollment: 120 participants
Actual Study Start Date: March 16, 2020
Estimated Primary Completion Date: November 22, 2021
Estimated Study Completion Date: November 22, 2021
(And by the way, phase 1 studies are not blinded, double-blinded, masked in any way, nor are they placebo-controlled, because the endpoint is just safety and lab values of the study vaccine. All that blinding and comparative stuff comes in later in phase 3 studies.)
The first big take away from this phase 1 study is that it is not over, meaning, that although it is no longer accruing new subjects, the data collection and subsequent evaluation will not be completed until sometime after November 22, 2021, roughly sixteen months hence.
That is pretty interesting in light of all the optimism about an FDA approved vaccine by late 2020 or early 2021 because if it’s Moderna’s vaccine that is approved/licensed, it will have been approved before even the phase 1 study had been completed. Yes, that’s a little disconcerting, but we’re in a pandemic, but not cutting any safety corners, so they say.
More on the sub groups/stratification
It looks to me that there was a three age-group stratification: 18-55, 56-70, and 71 and older. A second stratification was by dosage, 10, 25, 50, 100, and 250 mcgs. Each of the 13 sub-groups had between 10 and 15 participants.
The preliminary results of the study were reported in a NEJM article published on July 14, 2020, and linked to the bottom of the clinicaltrials.gov entry referenced above, but here is a direct link to the journal article.
So, what were the results?
The vaccine had some immunogenicity benefit (i.e. antibodies, titers which are surrogate endpoints to vaccine efficacy/protection). In terms of side effects, here what was said:
“Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.”
Actually, unless I am misreading the chart, I think the authors are understating the results. The way I read the chart, 100% percent of the study participants who took either 100 or 250 ug’s of the vaccine had a systematic symptom, the overwhelming majority of which were characterized as “moderate” (After the second injection). And 100% of the same groups had a local symptom, the majority of which were “moderate” with about 5% being considered severe, (also after the second injection.) The first injection also produced substantial local and systemic symptoms, but less than after the second shot.
(Hint: Remember these doses and their side effects during my discussion of the phase 3 study protocol, as I will be circling back to them)
And of course, the study just started four-plus months ago, and who knows what new or continuing symptoms/adverse effects might show up.
So, what was the authors’ conclusions?
“Conclusions: The mRNA-1273 vaccine-induced anti-SARS-CoV-2 immune responses in all participants and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).”
My translation: no one died yet, so let’s keep moving forward on this.
The Phase 2 studies
Actually, I could not find any information about the phase 2 studies. Given the fact that (a) the phase 1 study started in mid-March 2020 and is scheduled to continue until November 2021, (b) the results of the phase 1 study were just published two weeks ago, and (c) the announcement that the phase 3 study started yesterday, July 27, 2020, I am going to go out on a limb and say there weren’t any phase 2 studies.
But this is a pandemic, but no safety corners were cut.
The Phase 3 study
Here is the basic information about the study:
“Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 30000 participants
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older
Actual Study Start Date: July 27, 2020
Estimated Primary Completion Date: October 27, 2022
Estimated Study Completion Date: October 27, 2022”
here is the link to the study information on clinicaltrials.gov:
The important points: It started July 27, 2020, and is supposedly going to run until October 27, 2022, and accrue up to 30,000 subjects. It will be randomized and fully blinded.
The study will have three categories of outcomes they are looking at (my interpretation/restatement of what they are looking to find out):
1. Will the drug prevent people from getting the virus by comparing the post-injection infection rates between the vaccine group and the control group?
2. What kinds of adverse events the subjects have (and AE’s will be stratified in many different ways, which I will discuss later)
3. Lab value results in terms of antibodies and titers, i.e., the surrogate endpoints for the vaccine doing what it’s supposed to do, prevent people from contracting the virus (or as recently restated, you still catch it but won’t be as likely to kill you.)
Who can be in the study?
Well, it’s not quite as limited as the Phase 1 study which was just for healthy people. The phase 3 study is open to “Healthy adults or adults with pre-existing medical conditions who are in stable condition. A stable medical condition is defined as a disease not requiring significant change in therapy or hospitalization for worsening disease during the 3 months before enrollment.”
Who is excluded?
All kinds of immunocompromised patients of course, and interestingly, people who have had a significant reaction to a prior vaccine (“History of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a vaccine”). But since these kinds of reactions are so exceedingly rare, I wouldn’t expect that many people would be excluded on that basis (cough). But it is a voluntary study, so what kind of idiot would you have to be to volunteer to get an entirely new kind of vaccine if you had a significant reaction to a prior vaccine which had already been proven to be safe and effective (cough, sorry I must have a scratchy throat, but since I’m basically quasi isolating, I’m pretty sure it’s not the virus).
Of course, the big exclusions are kids and actively sick old people. Regrettably, those are the two groups which are most likely to be forced to get it (kids via an amendment to the ACIP vaccine schedule used by every state, and sick older adults because of their increased risk of death from the virus and their resulting fear).
And that is probably the biggest problem with the study if it is used as the sole basis for approval. It would not have been tested on the people most likely to get it. Granted, there are legitimate ethical reasons to do initial studies and even phase 3 studies with healthy or not actively sick adults. But usually, there would be further studies pre-approval/license. My guess is that this one study is going to be it for this vaccine before an application for approval/license is filed. Further, I am also guessing that the approval license application will be submitted before the conclusion of this phase 3 study, and even before the conclusion of the phase 1 study in November 2021. As has been oft said, what can possibly go wrong with giving a vaccine (or as here, a new type of vaccine) to very old people many of whom have multiple co-morbidities where the vaccine has not been tested in actively sick old people?
And speaking (again) of side effects, what’s the dose given in the vaccine arm?
“Participants will receive 1 intramuscular (IM) injection of 100 micrograms (ug) mRNA-1273 on Day 1 and on Day 29.”
That is the same 100 ug dose that produced mostly moderate local and systemic symptoms in 100% of the completely healthy 120 phase 1 subjects. Again, what could possibly go wrong with giving it to those who are not completely healthy?
I confess to being unclear about what exactly was meant by the phase 1 study’s use of a “moderate symptom” as opposed to a severe or mild one. Thankfully, the AE/symptom stratification is much more refined in the phase 3 study. Here is the breakdown of AE’s: “Number of Participants with Adverse Events (AEs) or Medically Attended AEs (MAAEs) Leading to Withdrawal [ Time Frame: Up to Day 759 (2 years after the second dose) ]; Number of Participants with Solicited Local and Systemic Adverse Reactions (ARs) [ Time Frame: Up to Day 8 (7 days after the first dose) and up to Day 36 (7 days after the second dose) ] Number of Participants with Unsolicited AEs [ Time Frame: Up to Day 57 (28 days after each dose)]”.
(Ok, so maybe it is just a smidgen better.)
Note that AE reporting as a stated “outcome measure” is limited to 28 days after each dose or 57 days after the first injection. I guess they think that any problem, local or systemic which happens on the 58th day or after is presumptively not a result of the vaccine so is not reported as an AE. (I know how much my vaccine concerned doc clients will be outraged by that.)
BUT HERE IS THE REALLY, REALLY BIG GOOD NEWS (really!):
The study will be true placebo controlled!
Here is the language:
“Placebo Comparator: Placebo
Participants will receive 1 IM injection of mRNA-1273-matching placebo on Day 1 and on Day 29. Biological: Placebo
0.9% sodium chloride (normal saline) injection”
This is huge. The biggest problem with vaccines according to the vaccine concerned is that they are not safety tested against a true placebo, but rather against another vaccine, or the test vaccine less the antigen. Therefore, it is impossible to know the actual safety profile of the study vaccine. The only safety conclusion that can be reached is a relative safety profile compared to some other vaccine. And since none of the ACIP required vaccines were safety tested against a placebo, there is nothing but relative safety data comparing one vaccine’s safety (or lack thereof) to another, from which you cannot make a safety analysis, according to the vaccine concerned medical and scientific professionals. Thus, the protocol which requires an actual real, inert placebo is, as I said, huge.
Alas, I have to point out that the Oxford trial protocol originally had a real placebo as well, (I learned that from Bobby Kennedy’s debate with Alan Dershowitz. If you haven’t seen it, here is a link to the post which has a link to the debate.https://rickjaffeesq.com/2020/07/27/the-kennedy-dershowitz-debate-must-see-tv/) but was changed to the meningitis vaccine as the control, which I am told is particularly noxious and harmful.
So, we will have to see if they stick to the actual inert placebo in the trials. If they don’t, it will have to be disclosed, I would think, but it will likely be buried in some footnote and further obscured in gobbledygook faux scientific language and justifications.
That is about all I can tease out of these documents, at least at a first pass, given my time constraints. The big problem I fear will be transparency. How much will the public really get to see the data? Not much I expect. It will be critical to follow this and the other studies very closely, and let’s see what happens.
The big tell/sign that the fix is in is if the protocol is amended to eliminate the saline placebo. If that happens, that means that the side effects are too severe and widespread to make the vaccine palatable to the public, so that’s when they would make the change to compare it to a more toxic vaccine and proclaim its (relative) safety. If they stick with the saline placebo, then let the chips fall where they may. But to my mind, the phase 1 study results do not bode well, and my bet is on them dumping the true placebo, no later than halfway through the study, with some scientific-sounding justification, but I hope I am proven wrong.
Rick Jaffe, Esq.