Conditions: Metformin Adverse Reaction Tolerance
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: yes

Brief summary:
Metformin is a safe and effective first-line drug for type 2 diabetes that is also widely recommended for weight loss and diabetes prevention. But, metformin is associated with gastrointestinal and other side effects which prevent its use in 10-20% of patients and appear to limit the usable dose in others. This study is an N-of-1 trial design that will recruit 20 previously metformin-intolerant patients for re-challenge with metformin in a double-blind scenario. In this setting, 'intolerant' means either unable to take metformin at all, or unable to increase the dose past 1,000 mg despite the treating physician's recommendation to do so. Patients will be assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of metformin extended release, followed by 500 mg metformin XR, 750 mg, and 1,000 mg metformin XR with each treatment period separated by a 2-week course of placebo. Initial treatment, placebo or metformin XR, will be decided randomly. At the end of each two-week treatment period, participants will complete questionnaires assessing overall satisfaction with the medication, gastrointestinal symptoms, and adherence. Six months after the conclusion of the intervention, patients will be asked if they are continuing metformin at a higher dose than upon entry to the trial. This trial has two aims. First, to test the hypothesis that medication satisfaction will be the same during periods of placebo treatment and during periods of treatment with the active drug. The second aim is to test the hypothesis that \> 30% of metformin-intolerant patients in an N of 1 crossover trial are able to tolerate higher-dose metformin at 6-months.

Detailed description:
Results have been presented in a single study arm as the order in which patients received drug or placebo was unique for each patient.

Arms:
arm 1: Patients will be assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of metformin extended release, followed by 500 mg metformin XR, 750 mg, and 1,000 mg metformin XR with each treatment period separated by a 2-week course of placebo. arm 2: Patients will be assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of placebo, followed by 500 mg placebo, 750 mg, and 1,000 mg placebo with each treatment period separated by a 2-week course of metformin XR in the same increments of dosage.

Interventions: intervention 1: Metformin Extended Release Oral Tablet intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Metformin hydrochloride extended release tablets in dosages of 250 mg, 500 mg, 750 mg, and 1,000 mg. Individual encapsulations of metformin will contain dosages of 250 mg or 500 mg. intervention 2: Placebo capsule

Protocol document:
Prot_SAP_000.pdf: 
 
 
IRB Protocol Number: 1706018342 
Clinicaltrials.gov ID: NCT03467763 
 
Protocol and Statistical Analysis Plan:  07/09/2018 
 
Title: Trial of an intervention to Improve Metformin Persistence and Adherence 
 
Coordinating Center: Weill Cornell Medicine, Department of Medicine 
 
Primary Investigator: Leon I. Igel, M.D. 
 
Coinvestigator: James H. Flory, M.D. 
 
 
Protocol 
Version 
IRB 
Approval 
Version 1 
01/29/2018 
Version 2 
07/09/2018 
 
 
 


Study Overview: 
 
This protocol outlines the design for a randomized controlled trial entitled, "Trial of 
Restarting and Tolerating Metformin (TreatMet)".  Metformin is a safe and effective first-
line drug for type 2 diabetes that is also widely recommended for weight loss and 
diabetes prevention. But, metformin is associated with gastrointestinal and other side 
effects which prevent its use in 10-20% of patients and appear to limit the usable dose 
in others. This study is an N-of-1 trial design that will recruit 20 previously metformin-
intolerant patients for re-challenge with metformin in a double-blind scenario. In this 
setting, 'intolerant' means either unable to take metformin at all, or unable to increase 
the dose past 1,000 mg despite the treating physician's recommendation to do so. 
Patients will be assigned to take their baseline medication regimen plus 2 weeks of 250 
mg per day of metformin extended release, followed by 500 mg metformin XR, 750 mg, 
and 1,000 mg metformin XR with each treatment period separated by a 2-week course 
of placebo. Initial treatment, placebo or metformin XR, will be decided randomly. At the 
end of each two-week treatment period, participants will complete questionnaires 
assessing overall satisfaction with the medication, gastrointestinal symptoms, and 
adherence. Six months after the conclusion of the intervention, follow-up will establish if 
patients are continuing metformin at a higher dose than upon entry to the trial. This trial 
has two aims. First, to test the hypothesis that medication satisfaction will be the same 
during periods of placebo treatment and during periods of treatment with the active 
drug. The second aim is to test the hypothesis that > 30% of metformin-intolerant 
patients in an N of 1 crossover trial are able to tolerate higher-dose metformin at 6-
months.  
 
Relevant Scientific Background: 
 
Despite 60 years of clinical use, and approximately 20 years in which it has been the 
consensus first-line drug for type 2 diabetes, there are still unresolved translational 
science questions about metformin. Metformin has only a 50% rate of use among 
patients with diabetes, and far lower rates of use in patients with obesity and pre-
diabetes. In all these groups, poor tolerability related to gastrointestinal side effects is 
seen as a significant barrier to use. Intolerance can result in non-persistence, poor 
adherence, or the inability to titrate the dose up to that shown to be efficacious in major 
studies. One question about metformin intolerance is how often it results from 
reproducible physical side effects and how often it results from subjective symptoms 
that are either transient or attributable to placebo effect ("psychogenic intolerance"). 
Anecdotally, some metformin-exposed patients experience dramatic, objective 
gastrointestinal side effects that preclude (or dose-limit) its use, while other patients 
experience vaguer malaise that may be psychogenic. Statin therapy provides a useful 
analogy: while some statin users experience objectively verifiable myopathy with 
creatine kinase elevations, others discontinue statin therapy due to much more 
subjective symptoms. Joy and colleagues found a group of eight patients with a history 
of statin intolerance could not reliably distinguish between statin and placebo in a 
crossover re-challenge study, and that half of these patients persisted with statin use 
long-term after the re-challenge.1 Particularly in diabetes prevention, the perception by 


patients that metformin is worsening their quality of life may be a substantial barrier 
to long-term use. Research is needed to characterize how often this concern is based 
on reproducible side effects and how often it is a form of placebo effect. For patients in 
whom it is due to placebo effect, simple interventions (for example, demonstrating that 
the side effects are the same with the drug and with a placebo) might eliminate this 
psychogenic intolerance and make the patient more comfortable with long term use of 
metformin. For patients who do have reproducible symptoms from metformin use, more 
research into the risk factors and causes for such side-effects is needed to support 
development of interventions to make metformin more tolerable.  
 
There are over 14 million unique prescriptions for metformin in the U.S annually, and it 
is widely regarded as a very safe medication for the treatment of type 2 diabetes 
mellitus; though side effects do occur. The most frequent adverse events attributable to 
metformin are primarily gastrointestinal, including nausea, diarrhea, and GI upset. 
Metformin contains a black-box warning for lactic acidosis, however cases of this 
occurring nearly are nearly non-existent. One study (Salpeter) found, "There is no 
evidence to date that metformin therapy is associated with an increased risk of lactic 
acidosis or with increased levels of lactate compared with other antihyperglycemic 
treatments if the drugs are prescribed under study conditions, taking into account 
contraindication".2 Furthermore, risk of hypoglycemia is near zero with metformin. The 
package insert for metformin produced by the FDA states, "hypoglycemia does not 
occur in patients receiving metformin alone under usual circumstances of use, but could 
occur when caloric intake is deficient, when strenuous exercise is not compensated by 
caloric supplementation, or during concomitant use with other glucose-lowering agents 
(such as sulfonylureas) or ethanol".  
 
From a pragmatic point of view, it has been proposed that for patients who are strongly 
motivated to use a medication but experience subjective discomfort when using it, an n-
of-1 placebo-controlled trial can be a therapeutic intervention. For patients who are 
having difficulty assessing whether their quality of life is worsened by exposure to a 
drug like metformin or a statin, undergoing a placebo-controlled double-blinded 
crossover study and finding that they cannot distinguish between the two could reduce 
concerns about purely subjective, placebo-driven side effects, and allow patients to use 
the drug without experiencing those effects. Conversely, if side effects are clearly 
reproducible with exposure to drug over placebo, patients and their providers could 
confidently conclude that the drug really is not tolerable for that patient. This idea has 
been developed to a limited extend in statin use, but has not been applied to diabetes 
treatments. 
 
Methods: 
 
Patients will be recruited at Weill Cornell Medicine and will be eligible if they have a 
diagnosis diabetes, pre-diabetes, or obesity, previously attempted to take metformin for 
one of these indications, and have a history of intolerance to metformin. Intolerance 
may manifest either as the inability to take metformin at all, or the inability to titrate the 
dose past 1,000 mg due to side effects. Intolerance will be defined based on the treating 


physician's assessment that a history of metformin intolerance (defined as the inability, 
due to side effects, to use metformin at the otherwise medically appropriate dose) 
exists, confirmed by the patient's recollection of the same history .  
 
Subject will be recruited that currently have a diagnosis of diabetes, pre-diabetes, or 
obesity, and possible related comorbidities, but who are ambulatory, independent, and 
neither seriously nor terminally ill.  
 
Electronic medical records will be reviewed for patients who have been prescribed 
metformin hydrochloride and for whom the medical record indicates that metformin 
intolerance occurred and limited the patient's ability to take metformin.  
 
Physicians involved in the clinical trial will identify eligible patients. Once identified, the 
physician will approach the patient in the clinic at their next appointment and discuss 
participation in the study. With the permission of other providers at WCMC, such as 
primary care providers, physicians involved in TreatMet or other study personnel in 
TreatMet may contact patients by telephone to invite them to participate in this study. 
Physicians will receive an email, or personal contact inquiring whether they are willing to 
give the investigators permission to contact specific patients, or to contact patients 
themselves. Only after obtaining physician approval, patients will be contacted via 
telephone to invite them to participate in TreatMet. Patients will be contacted during 
normal office hours. If a patient declines participation, they will not be contacted again. If 
patients do agree, an in-person meeting for written informed consent will be scheduled. 
Patients are free to opt-out at any point in this process.  
 
Study Design: 
 
This trial is a self-controlled, double blind crossover study enrolling patients with a clear 
history of metformin intolerance. Intolerance is defined here as the inability, despite the 
recommendations of the treating physician, either to take metformin at all, or to increase 
daily metformin dose beyond 1,000 mg. The study intervention is the addition of 250 
mg, 500 mg, 750 mg, and 1,000 mg of metformin daily, to the patient's existing regimen. 
Up to twenty patients will be enrolled for ten months. For one two-week block they will 
have 250 mg of metformin extended-release added to their existing regimen, followed 
by two-week blocks of 500 mg, 750 mg, and 1,000 mg metformin XR, each separated 
by two-week periods of placebo. The order of treatment assignments will be double-
blinded and randomized, except that the 250 mg, 500 mg, 750 mg, and 1,000 mg blocks 
will always occur in order, smallest to largest.  
 
Primary Objectives: 
 
For aim 1 of this study, the primary objective is to test the hypothesis that patients will 
have similar treatment satisfaction on metformin and on placebo. The primary outcome 
of this portion of the study will be the results of the Treatment Satisfaction Questionnaire 
for Medication. For aim 2 of this study, the primary objective is to test the hypothesis 


that > 30% of the patients enrolled in this study are able to tolerate higher-dose 
metformin at 6 months.  
 
Secondary Objectives: 
 
For aim 1, the secondary objectives are to test the hypotheses that scores on a 
gastrointestinal symptom questionnaire are not significantly different between placebo 
and intervention periods; that adherence is not significantly different between periods; 
and that the answer to the question 'Were you taking placebo or metformin for the past 
two weeks' is correct no more often than would be predicted by chance.  
 
Statistical Considerations: 
 
With respect to sample size for aim 1, by Lehr's approximation, a sample size of 16 
would be needed to identify a 1 standard deviation difference in the mean score on the 
Medication Treatment Satisfaction Questionnaire. The target sample size is 20 patients 
to account for possible patient dropout. With respect to sample size for aim 2, by Lehr's 
approximation, a sample size of 20 provides 95% confidence intervals of approximated 
+/- 20% around most reported percentages. If the reported rate of success in increasing 
metformin dose is 30%, the 95% confidence interval around that estimate will range 
from 10% to 50%. If the reported percentage is 0%, the 95% confidence interval will be 
approximately 0-15%. We think these are sufficiently precise estimates to help clinicians 
decide whether n-of-1 clinical trials are a useful intervention for overcoming metformin 
intolerance.  
 
Inclusion/ Exclusion Criteria:  
 
Patients will be eligible if they are between the ages of 18 and 100.  Patients will be 
recruited in an outpatient setting.  Subjects will be enrolled regardless of gender, though 
a 50:50 ratio of male to female subjects is desirable.  
Patients will be ineligible if they have a contraindication to metformin (ie, advanced renal 
or liver disease, a history of lactic acidosis attributed to metformin, or advanced heart 
failure). Pregnant women will be excluded from this study due to risk of confounding; 
pregnant women frequently have nausea and vomiting, changing over time, which if 
included may invalidate the results of the study.  
 
Assessing Safety and Efficacy: 
 
No data will be collected systematically to monitor safety or efficacy, only tolerability. 
However, the gastrointestinal symptom questionnaire will serve to quantify 
gastrointestinal adverse events every 2 weeks. Patients will be educated on potential 
side effects and risks of metformin and encouraged to both stop the medication and 
contact the investigators if they experience intolerable side effects or any severe 
adverse reactions  
 
Interim and Complete Stopping Rules: 


 
Due to the small sample size, short duration, and limited risks of this study, statistical 
stopping rules are not specified. Patients are encouraged to speak with their physicians 
and study coordinators regarding any medication-associated adverse events that may 
occur as a result of participation in this study.  
 
Adverse Events Collection: 
 
Adverse events that may cause termination or dropout of a subject include 
hypoglycemia, lactic acidosis, and severe gastrointestinal effects including severe 
nausea, vomiting, and diarrhea.  
 
Metformin has a well-established safety profile in this clinical setting and no active 
monitoring for adverse events is planned. Patients who are using diabetes drugs 
associated with hypoglycemia (sulfonylurea, insulin, or meglitinide) will be advised of 
the potential for metformin to increase risk of hypoglycemia by potentiating the action of 
those drugs, and to immediately report any occurrence of hypoglycemia both to the 
study team and to their regular physician  
 
Adverse events will be graded according to the "Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0" scale produced by the United States Department of 
Health and Human Services and the National Institutes of Health. The CTCAE scale 
rates potential adverse events on a scale from 1 to 5, and is a commonly accepted 
method of grading adverse events. All adverse events will be recorded on the Office of 
Research Integrity's "Adverse Event & IND Safety Reporting Cumulative Table". We will 
report all required adverse events and incidents to NYPH-WCM Patient Services, Risk 
Management, and/or the Department of Health.  
 
In addition to the IRB, all adverse events recorded during this trial will be reported to Dr. 
James Flory, and Dr. Leon Igel.  
 
 
1 Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (Single-
Patient) Trials for Statin-Related Myalgia. Annals of Internal Medicine. 2014;160(5):301-
310 
2 Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic 
acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 
2010;2010(4):Cd002967.