Metformin Adverse Reaction, Tolerance
Conditions
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.
Interventions
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.
DRUGPlacebo oral capsule
Placebo capsule
Sponsors
Agency for Healthcare Research and Quality (AHRQ)
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Patients, care providers, and investigators will be masked to the identity of the trial medication until the conclusion of the trial, and unblinding.
Intervention model description
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. 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
Yes
Inclusion criteria
* Diagnosis of diabetes, pre-diabetes, or obesity * Previously attempted to take metformin for an above indication * History of metformin intolerance (defined based on 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)
Exclusion criteria
* Contraindication to metformin (i.e, advanced renal or liver disease, history of metformin attributed lactic acidosis, or advanced heart failure) * Pregnant women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Satisfaction as Measured by the Treatment Satisfaction Questionnaire for Medication (TSQM II) | 4-months | The primary outcome of this portion of the study will be the global satisfaction subscale of the Treatment Satisfaction Questionnaire for Medication (TSMQ II). The TSQM II is a 12-question survey with four satisfaction domains: effectiveness, side effects, convenience and global satisfaction. Each domain is described by a single numeric score. For each of these domains the lowest possible score (less satisfaction, ie a worse outcome) is 0, the highest (more satisfaction, ie a better outcome) is 100. We report this score global satisfaction domain (ie, subscale). (Note that the global satisfaction score is not a synthesis of the various subscales associated with each domain. It is a subscale in its own right comprised of distinct questions.) |
| Number of Subjects Able to Tolerate Higher Dose of Metformin, | 6-months | For aim 2 of this study, the primary objective is to test the hypothesis \> 30% of the patients enrolled in this study are able to tolerate (continue taking) a higher-dose of metformin at 6 months than they were taking at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Reoccurring every 2-weeks for 4-months | For aim 1, the secondary objectives are to test the hypotheses that scores on a gastrointestinal symptom questionnaire are the same between between placebo and intervention periods; that adherence is the same 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. Each question in the Gastrointestinal Symptom Rating Scale (GSRS) is scored on scale from 1 to 7 with 1 being no discomfort at all and 7 being very severe discomfort. The GSRS has separate questions to separately assess each of a range of potential GI symptoms (abdominal pain, reflux, diarrhoea, indigestion and constipation). Each symptom area can be described with the mean score of its contributing questions (so that the range in each symptom area is also 1 to 7, with lower numbers being better) |
Countries
United States
Participant flow
Pre-assignment details
Please note that results have been presented in a single study arm as the order in which participants received drug or placebo was unique for many patients, so that reporting a separate arm for each sequence of drug and placebo exposure would have resulted in reporting individual level results, potentially compromising patient confidentiality.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Hydrochloride Extended Release and Placebo Participants took their baseline medication plus escalating doses of metformin in 250 mg increments, alternating with placebo in a randomized, double-blinded fashion.
Patients were 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.
Metformin Extended Release Oral Tablet: 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.
Patients were 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.
Placebo oral capsule: Placebo capsule | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation | 2 |
Baseline characteristics
| Characteristic | Metformin Hydrochloride Extended Release and Placebo |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized More Than One Race | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 3 Participants |
| Race/Ethnicity, Customized White | 6 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Number of Subjects Able to Tolerate Higher Dose of Metformin,
For aim 2 of this study, the primary objective is to test the hypothesis \> 30% of the patients enrolled in this study are able to tolerate (continue taking) a higher-dose of metformin at 6 months than they were taking at baseline.
Time frame: 6-months
Population: Results from 3 participants not analyzed as these participants were lost to follow-up or violated study protocol. Results are presented in a single study arm, as reporting a separate arm for each sequence of drug and placebo exposure would have resulted in reporting individual level results, and because this outcome occurs only once per patient after the end of all placebo and metformin exposure periods it could not reported as two arms (placebo versus metformin.)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin Hydrochloride Extended Release | Number of Subjects Able to Tolerate Higher Dose of Metformin, | 2 Participants |
Primary
Treatment Satisfaction as Measured by the Treatment Satisfaction Questionnaire for Medication (TSQM II)
The primary outcome of this portion of the study will be the global satisfaction subscale of the Treatment Satisfaction Questionnaire for Medication (TSMQ II). The TSQM II is a 12-question survey with four satisfaction domains: effectiveness, side effects, convenience and global satisfaction. Each domain is described by a single numeric score. For each of these domains the lowest possible score (less satisfaction, ie a worse outcome) is 0, the highest (more satisfaction, ie a better outcome) is 100. We report this score global satisfaction domain (ie, subscale). (Note that the global satisfaction score is not a synthesis of the various subscales associated with each domain. It is a subscale in its own right comprised of distinct questions.)
Time frame: 4-months
Population: The results from 3 participants were not analyzed as these participants were lost to follow-up or violated study protocol. Results are presented in two study arms, as reporting a separate arm for each sequence of drug and placebo exposure would have resulted in reporting individual level results, potentially compromising patient confidentiality. All patients contributed data to both arms except for 2 patients who had missing data during their placebo-exposed time.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin Hydrochloride Extended Release | Treatment Satisfaction as Measured by the Treatment Satisfaction Questionnaire for Medication (TSQM II) | 39.42 score on a scale | Standard Error 5.09 |
| Placebo | Treatment Satisfaction as Measured by the Treatment Satisfaction Questionnaire for Medication (TSQM II) | 51.92 score on a scale | Standard Error 4.57 |
Secondary
Change in Score of Gastrointestinal Symptom Rating Scale (GSRS)
For aim 1, the secondary objectives are to test the hypotheses that scores on a gastrointestinal symptom questionnaire are the same between between placebo and intervention periods; that adherence is the same 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. Each question in the Gastrointestinal Symptom Rating Scale (GSRS) is scored on scale from 1 to 7 with 1 being no discomfort at all and 7 being very severe discomfort. The GSRS has separate questions to separately assess each of a range of potential GI symptoms (abdominal pain, reflux, diarrhoea, indigestion and constipation). Each symptom area can be described with the mean score of its contributing questions (so that the range in each symptom area is also 1 to 7, with lower numbers being better)
Time frame: Reoccurring every 2-weeks for 4-months
Population: The results from 3 participants were not analyzed as these participants were lost to follow-up or violated study protocol. Results are presented in two study arms, as reporting a separate arm for each sequence of drug and placebo exposure would have resulted in reporting individual level results, potentially compromising patient confidentiality. All patients contributed data to both arms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin Hydrochloride Extended Release | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Diarrhea | 2.564 units on a scale | Standard Error 0.29 |
| Metformin Hydrochloride Extended Release | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Abdominal Pain | 2.308 units on a scale | Standard Error 0.21 |
| Metformin Hydrochloride Extended Release | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Constipation | 2.705 units on a scale | Standard Error 0.23 |
| Metformin Hydrochloride Extended Release | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Indigestion | 2.50 units on a scale | Standard Error 0.19 |
| Metformin Hydrochloride Extended Release | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Reflux | 1.885 units on a scale | Standard Error 0.24 |
| Placebo | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Indigestion | 2.296 units on a scale | Standard Error 0.26 |
| Placebo | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Reflux | 1.78 units on a scale | Standard Error 0.23 |
| Placebo | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Diarrhea | 2.346 units on a scale | Standard Error 0.26 |
| Placebo | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Constipation | 2.667 units on a scale | Standard Error 0.28 |
| Placebo | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) | Abdominal Pain | 2.346 units on a scale | Standard Error 0.17 |