Clinical trial NCT04055012
Conditions: Low Back Pain
Keywords: Low Back Pain Metformin Placebo
Sponsor: Gwendolyn Sowa
Start date: 2020-01-07; Completion date: 2023-12-15
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the current study is to determine the effects of metformin in non-diabetic patients with low back pain, and identify novel targets for future treatments

Detailed description:
Outcome measures were updated after the initial submission to clinicaltrials.gov. The outcomes were changed in the Institutional Review Board protocol but not updated on clinicaltrials.gov. These outcome measures have since been updated to reflect what was collected for the trial.

Arms: arm 1: High Dose Metformin Group (n=100). Subjects will receive metformin and will be instructed to take 2 tabs per day (1,000mg) for the first week then increase to 3 tabs per day (1,500mg) for the remaining 6 months. arm 2: Low Dose Metformin Group (n=100). Subjects will receive metformin and will be instructed to take 1 tab per day (1 metformin tab (500mg) for 6 months. arm 3: Placebo Group (n=100). Subjects will receive placebo and will be instructed to take either 2 tabs per day for the first week then increase to 3 tabs per day for the remaining 6 months OR take 1 placebo tab for 6 months. arm 4: Control Group (n=100). Subjects will be told that they are in the wait-list control group. They will have a 3 month "waiting period" before they will be randomized again to a treatment group. They will be randomized to one of the previous groups.
Interventions: intervention 1: Metformin intervention 2: Placebo
Intervention descriptions: intervention 1: 500mg tabs of Metformin Extended Release intervention 2: Placebo Tabs

Protocol documents:
ICF_002.pdf: 
Official Title:  Effects of Metformin on Low Back Pain 
ClinicalTrials.gov ID (NCT number): NCT04055012  
Document Date: 05/17/2022 
 
 


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Metformin and Beyond: Individualizing Care for Low Back Pain
This summary provides basic information to help you decide whether to consent or not to 
participate in this study.  More detailed information is provided in the following pages of this 
document. If you have any questions, please be sure to ask the research team.
The purpose of this voluntary research is to determine if Metformin improves low back pain and 
to examine what characteristics are associated with response to the study product. 
Study Procedures will take place during study visits.  You may have up to 6 study visits.  The 
procedures include: 

Taking Metformin or placebo for 6 months

Providing blood, stool, & saliva samples 

Completing questionnaires and an interview 

Completing a 10-meter walking speed test 
How long is my participation? You may be enrolled in the study for up to 15 months.
The risks of this study include the possibility of:
1. Potential breach of confidentiality
2. Side effects from Metformin including gastrointestinal side effects.  
For more details about risks, please see page 8 of the consent document.
Benefit: Should Metformin have a positive effect on back pain, it is possible that you may 
receive some benefit from the study product, however, such a benefit cannot be guaranteed.  
Compensation: You may receive up to $250 for participating in this study 
For more information continue reading this document or contact the research team. Contact 
information is provided on the following page.


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CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY
TITLE:
Metformin and Beyond: Individualizing Care for Low Back Pain  
SOURCE OF SUPPORT:  UPMC Immune Transplant and Therapy Center
You may be eligible to take part in a research study.  This form gives you important information 
about the study.  It describes the purpose of the study, and the risks and possible benefits of 
participating in the study.  
Please take time to review this information carefully.  After you have finished, you should talk to 
the researchers about the study and ask them any questions you have.  You may also wish to talk 
to others (for example, your friends, family, or other doctors) about your participation in this 
study.  If you decide to take part in the study, you will be asked to sign this form.  Before you 
sign this form, be sure you understand what the study is about, including the risks and possible 
benefits to you.
Your physician may be involved as an investigator in this research study. Before agreeing to 
participate, or at any time during your study participation, you may discuss your care with 
Principal Investigator:
Gwendolyn Sowa, MD
3471 Fifth Avenue, Suite 910
Pittsburgh, PA 15213
Phone:   (412) 648-6979
Megan Cortazzo, MD
Anthony Delitto, PhD
Eric Helm, MD
Suehun Ho, MD
Oscar Marroquin, MD 
Barbara Methe, PhD 
Alison Morris, MD, MS 
Petr Pancoska, PhD 
Nam Vo, PhD
Co-Investigators:
Lauren Wilcox, CCRP
Study Coordinator:
Phone:  (412) 692-2084
kesslerl@upmc.edu
Sarah Igwe, BS
igweso@upmc.edu


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another doctor who is not associated with this research study. You are not under any obligation 
to participate in any research study offered by your physician.
Description:
Low back pain is one of the most common musculoskeletal conditions requiring medical care 
and contributing to patient impairment and disability, with over 25% of the general population 
reporting low back pain at any given time and a lifetime incidence exceeding 80%. However, the 
care of low back pain represents one of the greatest challenges facing musculoskeletal care 
today. With increasing interest in the beneficial effects of metformin, the favorable side effect 
profile and low cost make metformin an attractive therapeutic candidate for the treatment of low 
back pain.
You are being asked to participate in a research study in which we will investigate if Metformin 
improves low back pain.  Currently, Metformin is not approved by the FDA for treatment of low 
back pain.  However, Metformin is an FDA approved medication for type 2 diabetes mellitus.  
For this double blind, wait-list controlled and placebo-controlled study, we will compare results 
from individuals who are randomized to take metformin for 6 months to those who take a 
placebo. We will also compare those results to individuals who wait 3 months to be randomized 
(wait-list control group).  The purpose of the placebo is to see if there is a difference between 
metformin and placebo. To account for the placebo effect, we have introduced the wait list 
control group.  You will not be eligible if you refuse randomization to the wait list control group.
Who can take part in this study?
Patients who have been diagnosed with low back pain are being invited to participate in this 
study.  Individuals invited to participate in this study must be over the age of 18 and if female, 
cannot be pregnant.  
How many people (subjects) are expected to take part in this study?
Approximately 400 people are expected to participate in this trial.  
What procedures will be performed for research purposes?
If you decide to take part in this research study, you will undergo the following procedures. The 
following ‘screening procedures’ will determine if you are eligible to take part in this research 
study.
Visit 1 – Screening and Baseline Procedures (Day 0)

After you sign the informed consent, you will undergo the screening process.  You will 
meet with a clinical research coordinator who will ask about your demographics, medical 
history and medications that you are taking.  You will also be asked questions about your 
current living situation and functional status.   Some additional questions may be asked 
about alcohol, drug, and tobacco use. 

Blood will be drawn (approximately 55.5ml or 3.7 tablespoons) from a vein in your arm.  


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If you are a woman capable of bearing a child, an extra 5ml of blood will also be 
collected to test for pregnancy. This is done prior to starting the study product to avoid 
risk to a fetus. A portion of the blood collected will be sent to a UPMC laboratory to 
make sure that it’s safe for you to enter the study.  If these lab values clinically 
significant, we will inform you and will recommend following-up with your primary care 
doctor.  The remaining blood will be used as part of this research study will be examined 
for research purposes.    

If you have taken NSAIDS (nonsteroidal anti-inflammatory drugs such as Aspirin or 
Ibuprofen, or Naproxen) within 7 days of screening visit, some blood samples will be 
collected after you have been off of NSAIDS for at least 7 days.  This could result in an 
extra visit and an additional 6.5 ml of blood being collected. 

You will be asked to provide a saliva sample for genetic analysis and a second saliva 
sample for microbiome analysis (looking at the organisms in your mouth). You will also 
be asked to provide a stool sample for microbiome analysis (looking at the organisms in 
your gut).  If saliva is not collected for genetic analysis during the baseline visit, it may 
be collected at a follow-up visit. 

You will be asked to complete a series of questionnaires that look at things such as pain, 
disability, anxiety, and general health.  You will also be asked to complete a 10-meter 
walking speed test.  

To confirm eligibility, it is possible that a study physician will need to complete a brief 
exam. If you meet all the inclusion and exclusion criteria, you will be assigned randomly 
(by chance) to one of the following groups: 
Metformin/Placebo Group
3 Month Wait List Group 
You will be instructed to take either a placebo or 
metformin as prescribed.  The study product will 
be one of the following:
-Metformin (1,500mg)
-Metformin (500mg)
-Placebo: at either a high dose (3 tabs) or low dose 
(1 tab)
You will not be prescribed a study product until your 
month 3 visit.  At your month 3 visit, you will be 
randomized to receive one of the following:   
-Metformin (1,500mg)
-Metformin (500mg)
-Placebo: at either a high dose (3 tabs) or low dose (1 
tab)
75% chance of being randomized to this group at 
the baseline visit.  The ratio of subjects 
randomized to metformin and placebo is 2:1.
25% chance of being randomized to this group at the 
baseline visit.
Complete the following follow-up visits:
Month 3
Month 6
Month 12
Complete the following follow-up visits:
Month 3
Month 6 
Month 9
Month 15

Subjects have a 1:1:1 ratio or 33.3% chance of being randomized into each study group.

The placebo looks just like Metformin but contains no active medication. Neither you, 
nor the physicians taking care of you, or the research investigators, will know which 
study product you are receiving.  


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o
You will be instructed to take the tablets as described above for a total of 6 
months.
o
Study product will be provided to you in pre-packaged blister packs containing 
one of the following:

High Dose Metformin Group:  3 metformin tabs

Low Dose Metformin Group: 1 metformin tab

High Dose Placebo Group:  3 placebo tabs 

Low Dose Placebo Group: 1 placebo tab

Note:  For the high dose groups, you will take 2 tabs per day for the first 
week and then increase to 3 tabs per day for the remainder of the 6 
months.

Depending on the availability of the results from the blood tests, you may not be 
randomized during this visit.

The study product will be given to you free of charge during your participation.

This visit is approximately 2 hours in length.  It will take place at a UPMC Facility. 

If it is determined that you do not meet the eligibility criteria, biosamples collected 
during this visit will be retained for analysis. 
Follow-Up Visits for Metformin and Placebo Groups Only
Study Product Distribution  

As soon as your eligibility is confirmed, your study product will be mailed to your house. 
You will be instructed to take the study product as prescribed.

If you had taken NSAIDS within 7 days of the screening visit, you will be asked to come 
back into the study center to collect blood samples that could not be collected during your 
screening visit. 
Month 3 visit  – Follow-Up Visit1 1 for Metformin and Placebo Groups 

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes, and if you’ve experienced any side effects.

Blood will be drawn (approximately 3.7 tablespoons) from a vein in your arm.  A portion 
of the blood collected will be sent to a UPMC laboratory to collect labs examining your 
response to the study product.  The remaining blood will be used as part of this research 
study and will be examined for research purposes.  

Stool sample for microbiome analysis.  

Saliva sample for microbiome analysis

Series of questionnaires that look at things such as pain, disability, anxiety, general 
health, and medication compliance. 

You will be asked to complete a 10-meter walking speed test. 

This visit is approximately 2 hours in length. 
Month 6 visit  – Follow-Up Visit 2 for Metformin and Placebo Groups 

Study product will be discontinued at this time.  You will be asked to return any unused 
study product.  

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes, and if you’ve experienced any side effects.


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
Blood will be drawn (approximately 3.7 tablespoons) from a vein in your arm.  A portion 
of the blood collected will be sent to a UPMC laboratory to collect labs examining your 
response to the study product.  The remaining blood will be used as part of this research 
study and will be examined for research purposes.  

Stool sample for microbiome analysis. 

Saliva sample for microbiome analysis 

Series of questionnaires that look at things such as pain, disability, anxiety, general 
health, and medication compliance. 

You will be asked to complete a 10-meter walking speed test.  

This visit is approximately 2 hours in length. 
Month 12 visit  – Follow-Up Visit 3 for Metformin and Placebo Groups 

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes, and if you’ve experienced any side effects.

Blood will be drawn (approximately 2.7 tablespoons) from a vein in your arm.  The blood 
will be used as part of this research study and will be examined for research purposes.  

Stool sample for microbiome analysis.  

Saliva sample for microbiome analysis

Series of questionnaires that look at things such as pain, disability, anxiety, and general 
health.

You will be asked to complete a 10-meter walking speed test.  

This visit is approximately 2 hours in length. 
Follow-Up Visits for 3 Month Wait List Group Only
If you had taken NSAIDS within 7 days of the screening visit, it is possible that you will have to 
come in for an additional visit to collect some of the blood samples once you’ve been off 
NSAIDS for at least 7 days. 
Month 3 visit  – Follow-Up Visit 1 for Control Group 

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes.

Blood will be drawn (approximately 3.7 tablespoons) from a vein in your arm.  A portion 
of the blood collected will be sent to a UPMC laboratory to collect labs confirming it is 
safe for you to take the study product.  If you are a woman capable of bearing a child, an 
extra 5ml of blood may also be collected for a pregnancy test.  The remaining blood will 
be used as part of this research study and will be examined for research purposes.  

Stool sample for microbiome analysis.

Saliva sample for microbiome analysis.   

Series of questionnaires that look at things such as pain, disability, anxiety, and general 
health.

You will be asked to complete a 10-meter walking speed test.  

Once your eligibility has been confirmed, you will be randomized to receive either 
Metformin or Placebo.  Neither you, the investigators, or the study staff will know what 
you are taking. You will be instructed to take the study product as prescribed.

This visit is approximately 2 hours in length. 


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Study Product Distribution    

As soon as your eligibility is confirmed, your study product will be mailed to your house. 
You will be instructed to take the study product as prescribed.
Month 6 visit  – Follow-Up Visit 2 for Control Group 

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes, and if you’ve experienced any side effects.

Blood will be drawn (approximately 3.7 tablespoons) from a vein in your arm.  A portion 
of the blood collected will be sent to a UPMC laboratory to collect labs examining your 
response to the study product.  The remaining blood will be used as part of this research 
study and will be examined for research purposes.  

Stool sample for microbiome analysis.  

Saliva sample for microbiome analysis

Series of questionnaires that look at things such as pain, disability, anxiety, general 
health, and medication compliance. 

You will be asked to complete a 10-meter walking speed test.

This visit is approximately 2 hours in length. 
Month 9 visit  – Follow-Up Visit 3 for Control Group 

Study product will be discontinued at this time.  You will be asked to return any unused 
study product.  

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes, and if you’ve experienced any side effects.

Blood will be drawn (approximately 3.7 tablespoons) from a vein in your arm.  A portion 
of the blood collected will be sent to a UPMC laboratory to collect labs examining your 
response to the study product.  The remaining blood will be used as part of this research 
study and will be examined for research purposes.  

Stool sample for microbiome analysis.  

Saliva sample for microbiome analysis

Series of questionnaires that look at things such as pain, disability, anxiety, general 
health, and medication compliance.

You will be asked to complete a 10-meter walking speed test.  

This visit is approximately 2 hours in length. 
Month 15 visit  – Follow-Up Visit 4 for Control Group

You will meet with a clinical research coordinator who will ask about your health, any 
medication changes, and if you’ve experienced any side effects.

Blood will be drawn (approximately 2.7 tablespoons) from a vein in your arm.  The blood 
will be used as part of this research study and will be examined for research purposes.  

Stool sample for microbiome analysis.  

Saliva sample for microbiome analysis

Series of questionnaires that look at things such as pain, disability, anxiety, and general 
health.

You will be asked to complete a 10-meter walking speed test.  

This visit is approximately 2 hours in length. 


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It is possible that some study activities may be conducted remotely.  For example, you may 
complete some of the questionnaires via the internet on your personal device or a device of your 
choosing. 
Blood Collection:  The blood collected during this study for research purposes will be used as 
part of this research study and will be examined for serum biomarkers (molecules found in 
biological fluids) and may be used by the investigators to help them to have a better 
understanding of a relationship between low back pain and metformin.  Genetic analysis, 
including whole genome sequencing, will also be conducted to analyze genes associated with 
low back pain.  The remainder of these samples will be stored indefinitely within the jurisdiction 
of UPMC and the University of Pittsburgh under the direction of the Principal Investigator of 
this research, Dr. Gwendolyn Sowa.  These samples may be used in future research related to 
back pain.  It is possible that these samples may be shared with other investigators at some point 
in the future, but samples would be shared without your identifiable information.  The results of 
any analysis of these samples will not be given to you as they are being drawn for research 
purposes only and will have no impact on your clinical care.
Blood collected and sent to the UPMC Clinical Laboratory will be reported back to you if 
medically necessary.  These values may also be put into your medical records. This includes 
results of pregnancy tests.
Saliva Collection:  A saliva sample will be collected for genetic analysis of genes related to pain 
(collected once) and an additional saliva sample will be completed for microbiome analysis 
(collected at each visit).  The microbiome is the bacterial make-up of your mouth.  You will be 
provided with saliva collection kits.  You will be asked to spit into the clear plastic tube until the 
saliva sample reaches the “fill line.”  This should take no more than 10 minutes for each kit.  
Stool Collection:  A stool sample will be collected for microbiome analysis.  The microbiome is 
the bacterial make-up of your stool.  You will be instructed on how to collect a stool specimen at 
home. You will receive instructions and a container, which is placed on your toilet, so that you 
can collect the stool and place a small amount of stool in a special tube. You will be given a pre-
paid envelope and supplies to collect and mail the sample back to our center.
Information regarding your health may be collected from your medical records.  Information 
collected from your medical records may be matched to your biosamples.  Information collected 
as part of this study may also be compared to results from other studies conducted by the 
investigators.  
Restricted Medications
The following medications are restricted during your participation in this study:

Oral or injected steroids

Nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, 
naproxen 

Diabetic medications such as sitagliptin, saxagliptin, linagliptin, alogliptin, 
sitagliptin with metformin

Carbonic anhydrase inhibitor such as topiramate, zonisamide, acetazolamide, 
dichlorphenamide, methazolamide

Cimetidine


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Follow-Up Phone Calls
A member of the study team will call you on the phone after you start taking the study 
product.  You will receive a phone call week 1, week 2, and week 4 after you start the study 
product.  You will be asked if you are experiencing any side effects and how you are feeling.  
Study Risks
Metformin – It is possible that you may be randomized to receive metformin. Common side 
effects include diarrhea, nausea/vomiting, flatulence, asthenia (lack of energy), indigestion, 
abdominal discomfort, anorexia, headache, or metallic taste in your mouth.  Serious reactions 
include lactic acidosis (buildup of lactate in the body), anemia, megaloblastic anemia (abnormal 
red blood cells), and hepatotoxicity (damage to the liver).  These risks will be evaluated by blood 
tests.
As is possible with any drug, you may have an unexpected allergic reaction, including severe 
immediate reactions.  Early symptoms of allergic reaction are often related to the skin, with 
flushing (warmth and redness of the skin), itching (often in the groin or armpits), and hives as 
common initial findings.  These symptoms are often accompanied by anxiety, and sometimes a 
rapid irregular pulse.  If the throat and tongue swell, this will result in hoarseness, difficulty 
swallowing, and difficulty breathing.  Symptoms of rhinitis or asthma may occur causing a runny 
nose, sneezing, and wheezing, which may worsen the breathing difficulty.  Vomiting, diarrhea, 
and stomach cramps may develop.  About 25% of the time, subjects with an allergic reaction 
may experience a drop in blood pressure, lightheadedness, or even loss of consciousness. If you 
experience symptoms of an allergic reaction while participating in the study, go to the 
emergency room or seek other immediate medical attention and contact study team when safe to 
do so.  
There is a risk of hypoglycemia (low blood sugar). Symptoms of hypoglycemia may include 
shakiness, dizziness, sweating, hunger, irritability, nervousness, and headache.  If you report 
symptoms of hypoglycemia, extra safety labs may be obtained. Safety labs are collected at every 
visit while you are taking the study product. If you develop diabetes while on the study product, 
you will be referred to your Primary Care Physician (PCP) to manage the diabetes. If you 
develop diabetes during the course of the study, you may not be removed from the study unless 
your treating physician requests discontinuation of the study product based on their treatment 
plan.
While taking Metformin, radiologic studies with dye can increase the risk of lactic acidosis.  
Symptoms of lactic acidosis may be nonspecific (eg, abdominal pain, malaise, muscle ache, 
respiratory distress, somnolence); severe cases may also present with hypothermia, hypotension 
and resistant bradyarrhythmias (disturbance in the heart rhythm in which the heart rate is 
abnormally slowed.)  If you are to undergo a procedure involving the administration of contrast 
dye, the study drug should be discontinued for 48 hours. 
You should avoid excessive alcohol while taking the study product.
  
Blood Draw - Likely risks of drawing blood from your arm may cause pain and/or bruising. On 
rare occasions infection or lightheadedness can occur.


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Saliva Sample – There are no anticipated risks associated with collection of the saliva sample. 
Stool Sample – There are no anticipated risks associated with collection of the stool sample.
Questionnaires - It is possible that you may become frustrated or experience anxiety during the 
screening interview and/or completion of questionnaires.  To minimize the discomfort associated 
with the screening tests/interview, we will be using standard questionnaires that are widely used 
in clinical practice.  We are having trained staff members conduct our sessions, and breaks will 
be allowed as necessary. 
Risks of Genetic Testing - The purpose of genetic testing for this study is to find unknown genes, 
learn how genes work, and advance our understanding of the relationship between genetics and 
low back pain. The goal is not to determine a person's susceptibility to any inherited disorder. 
Therefore, genetic test results will not be given to your doctor and will not be placed in your 
medical records. You will not receive your own test results because right now, no one knows 
whether the results provide useful information about your health or treatment. In this study, all 
genetic samples are stored without personal identification information and all specimens are 
labeled with a unique non-identifying number.   However, it is possible that if the results of your 
genetic testing were to become known, that could affect your future plans for children, family 
relationships, or ability to be insured or employed.  
The risks associated with gene studies include the potential for a breach of confidentiality which 
could affect future insurability, employability, or reproduction plans, or have a negative impact 
on family relationships and/or result in paternity suits or stigmatization.
In addition, there is a Federal law, called the Genetic Information Nondiscrimination Act 
(GINA), that generally makes it illegal for health insurance companies and group health plans to 
use genetic information in making decisions regarding your eligibility or premiums. GINA also 
makes it illegal for employers with 15 or more employees to use your genetic information when 
making decisions regarding hiring, promoting, firing, or setting the terms of employment. This 
new Federal law does not protect you against genetic discrimination by companies that sell life, 
disability, or long-term care insurance. GINA also does not protect you against discrimination 
based on an already-diagnosed genetic condition or disease.
Your research data/samples may be shared with investigators conducting other research; this 
information will be shared without identifiable information.  These research data/samples may 
contribute to a new discovery or treatment.  In some instances, these discoveries or treatments 
may be of commercial value and may be sold, patented, or licensed by the investigators and the 
University of Pittsburgh for use in other research or the development of new products.  You will 
not retain any property rights, nor will you share in any money that the investigators, the 
University of Pittsburgh, or their agents may realize.
The data, samples, and genetic data generated from samples may be shared with other 
researchers and with federal repositories, in a de-identified manner (without identifiers). The 
data, samples, and genetic data obtained from this study may also be combined with other 
databases in which the PI of this study is listed as an investigator or PI.


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Risk related to placebo - Risks of placebo include allergy to component that makes up the 
placebo.
Risk related to pregnancy- Metformin is considered a pregnancy category B medication.  
However, there is no current data regarding metformin and pregnancy, so the risks are unknown.   
To avoid risk to the fetus, it is important that you (for female participants), or your female sexual 
partner (for male participants), not become pregnant while you are participating in this research 
study. Please use an effective preventative measure (for example, birth control pills, condoms, 
other barrier methods, etc) while taking the study product.  However, please be advised that 
avoiding sexual activity while taking the study product is the only certain method to prevent 
pregnancy.  If you or your partner become pregnant while being enrolled in this study, please let 
the study staff know immediately.  
Breach of confidentiality is a possible risk of data collection and collection of biosamples. The 
information gathered will be stored on secure online servers and in locked filing cabinets/offices 
in order to prevent breach of confidentiality. Biosamples will be stored without identifiers and 
with subject ID only.  Every precaution will be taken to maintain confidentiality, but total 
confidentiality cannot be guaranteed.  
As with any experimental procedure, there may be adverse events or side effects that are 
currently unknown and certain of these unknown risks could be permanent, severe or life-
threatening.
Risk of data collection via the internet - Although every reasonable effort has been taken, 
confidentiality during Internet communication activities cannot be guaranteed and it is possible 
that additional information beyond that collected for research purposes may be captured and used 
by others not associated with this study.
Possible Benefits 
Should Metformin have a positive effect on back pain, it is possible that you may receive some 
benefit from the study product, however, such a benefit cannot be guaranteed.  Individuals 
assigned to the placebo group are expected to receive no direct benefit from study participation. 
However, due to the placebo effect, it is possible that subject's randomized to receive placebo 
may also see some improvement. Your participation in this study may help us to improve our 
care of those who experience low back pain in the future.  Such improvements in care would 
benefit the individual and society at large. 
New Information
You will be promptly notified if any new information we learn during this research study may 
cause you to change your mind about continuing to participate in the study.
Privacy & Confidentiality
Any information about you obtained from this research will be kept as confidential (private) as 
possible.  All paper records related to your involvement in this research study will be stored in a 
locked file cabinet in a locked office of the department of Physical Medicine and Rehabilitation. 
Your identity will be included in these research records.  Your biosamples will be stored with a 


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subject ID number.  The linkage code linking the ID to your name will be kept in a separate, 
locked database on a restricted network drive.  The results from the “safety lab” analysis and 
pregnancy test results (if applicable) will be placed in your medical record.  You will not be 
identified by name in any publication of the research results unless you sign a separate consent 
form giving your permission (release).
The investigators may continue to use and disclose your information for an indefinite period of 
time. Samples collected for research purposes will be stored indefinitely.  
It is possible that we may use the information obtained from this study (including your biological 
specimens) in other research studies examining outcomes after back pain.  This research 
information, including genetic information and biological specimens, may also be shared with 
other researchers here and at other research centers, but those researchers will never be provided 
with any personal identifiers that would allow them to learn your identity.  Information collected 
as part of this study may also be compared to results from other studies conducted by the 
investigators.  
Who will have access to identifiable information related to my participation in this 
research study?
In addition to the investigators listed on the first page of this authorization (consent) form and 
their research staff, the following individuals will or may have access to identifiable information 
(which may include your identifiable medical information) related to your participation in this 
research study: 
Authorized representatives of the University of Pittsburgh Office of Research Protections may 
review your identifiable research information (which may include your identifiable medical 
information) for the purpose of monitoring the appropriate conduct of this research study. 
Authorized representative of the University of Pittsburgh Clinical and Translational Science 
Institute may review your identifiable research information (which may include your identifiable 
medical information) for the purpose of performing data analysis.
In unusual cases, the investigators may be required to release identifiable information (which 
may include your identifiable medical information) related to your participation in this research 
study in response to an order from a court of law.  If the investigators learn that you or someone 
with whom you are involved is in serious danger or potential harm, they will need to inform, as 
required by Pennsylvania law, the appropriate agencies.  
Authorized representatives of the sponsor of this research study, UPMC Office of the Medical 
and Scientific Officer, may review and/or obtain identifiable information (which may include 
your identifiable medical information) related to your participation in this research study for the 
purpose of monitoring the accuracy and completeness of the research data and for performing 
required scientific analyses of the research data.  Authorized representatives of the study sponsor 
may also be present during your participation in this research study.  The investigators involved 
in the conduct of this research study may receive funding from the sponsor to perform the 
research procedures and to provide the sponsor with identifiable research and medical 
information related to your participation in the study. 


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Authorized representatives of UPMC hospitals or other affiliated health care providers may have 
access to identifiable information (which may include your identifiable medical information) 
related to your participation in this research study for the purpose of (1) fulfilling orders, made 
by the investigators, for hospital and health care services (e.g., laboratory tests, diagnostic 
procedures) associated with research study participation; (2) addressing correct payment for tests 
and procedures ordered by the investigators; and/or (3) for internal hospital operations (i.e. 
quality assurance).
Authorized representative of US and foreign government regulatory agencies such as the U.S. 
Food and Drug Administration (FDA) may review and/or obtain your identifiable information 
(which may include your identifiable medical record information) related to your participation in 
this research study for the purpose of monitoring the accuracy of the research data. While these 
agencies understand the importance of maintaining the confidentiality of your identifiable research 
and medical record information, UPMC and the University of Pittsburgh cannot guarantee the 
confidentiality of this information after it has been obtained by them.
Per University of Pittsburgh policy all research records must be maintained for at least 7 years 
following final reporting or publication of a project.
Will this research study involve the use or disclosure of my identifiable medical 
information?
This research study may involve the recording of past and/or current identifiable medical 
information from your hospital and/or other (e.g., physician office) records.  The information 
that will be recorded will be limited to information concerning your eligibility to participate in 
this research study as well as collection of information necessary to address the study goals.  
May I have access to my medical information that results from my participation in this 
research study?
In accordance with UPMC Notices of Privacy Practices document that you have been provided, 
you are permitted access to information; however, your access to the study specific information 
will not be available for review until the end of the study. At that time, you have the right to see 
and copy the medical information collected during the study for as long as that information is 
contained within your medical records and/or filed with your health care provider.
FDA Clinical Trial Registry
A description of this clinical trial is available on http://www.clinicaltrials.gov, as required by US 
Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.
Withdrawal from Study Participation
You can, at any time withdraw from this research study; you can also withdraw your 
authorization for us to use your identifiable medical information for the purposes described 
above. This means that you will also be withdrawn from further participation in this research 
study. Any identifiable research or medical information obtained as part of this study prior to the 
date that you withdrew your consent will continue to be used and disclosed by the investigators 
for the purposes described above.


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To formally withdraw from this research study, you should provide a written and dated notice of 
this decision to the principal investigator of this research study at the address listed on the first 
page of this form. Your decision to withdraw your consent for participation in this research study 
will have no effect on your current or future medical care at a UPMC hospital or affiliated health 
care provider or your current or future relationship with a health care insurance provider.
If you decide to withdraw from study participation after you have received the study drug, you 
should participate in additional monitoring follow-up procedures that are being conducted to 
measure the safety of the study drug.
All biosamples collected will be retained unless requested in writing that they be destroyed.  
Could I be removed from the study?
It is possible that you may be removed from the research study by the researchers if, for 
example, the investigator feels that it isn’t in your best interest to continue, for safety reasons, or 
if you are no longer eligible to participate.  We may request follow-up for safety reasons.
Will I be paid if I take part in this research study?
Yes, you will be compensated a total of $50 ($40 for completing the visit and $10 after stool 
sample is received) for completing the questionnaires, assessments, and sample collection during 
each visit. 
Individuals randomized to the placebo/metformin groups may receive up to $200 for completion 
of all study visits.  Individuals randomized to the 3 month wait list group may receive up to $250 
for completion of all study visits. If needed, parking will be validated. You will be paid on a 
reloadable debit card. Your name, address, and social security number will be released to the 
Accounting Office. All compensation is taxable income to the participant.  If you receive $600 or 
more in a calendar year from one organization, that organization is required by law to file a Form 
1099 – Miscellaneous with the IRS and provide a copy to the taxpayer. Individuals who do not 
provide a social security number may still participate in the research, but the IRS requires that 
24% of the payment be sent by the institution to the IRS for ‘backup withholding;’ thus you 
would only receive 76% of the expected payment.
Your biological samples may lead, in the future, to new inventions or products.  If the 
investigators are able to develop new products from the research use of your biological sample, 
there are currently no plans to share with you any money or other rewards that may result from 
the development of these new products.
Is there a cost to participate in this study?
No, there is no cost to participate in this study.  All tests and procedures outlined in this consent 
form will be paid for by the study. All study medications, tests and procedures are covered by the 
research study.  However, your insurance will be billed for your normal, standard clinical care.  
Who will pay if I am injured as a result of taking part in this study?
If you believe that the research procedures have resulted in an injury to you, immediately contact 
the Principal Investigator who is listed on the first page of this form. Emergency medical 


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treatment for injuries solely and directly related to your participation in this research study will 
be provided to you by the hospitals of UPMC. Your insurance provider may be billed for the 
costs of this emergency treatment, but none of those costs will be charged directly to you. If your 
research-related injury requires medical care beyond this emergency treatment, you will be 
responsible for the costs of this follow-up care. At this time, there is no plan for any additional 
financial compensation. You do not, however, waive any legal rights by signing this form.
CONFIDENTIALITY AND AUTHORIZATION TO RELEASE YOUR PROTECTED 
HEALTH INFORMAITON:
We are also requesting your authorization or permission to review your medical records to 
determine whether you meet the conditions for participation in this study, to compare your 
earlier test results to the findings from this study, and if possible, to use your previous exam 
results in place of, or in addition to, some of the exams needed for this study.  We will obtain the 
following information: your diagnosis, age, past medical history, diagnostic procedures such as 
x-rays and MRIs, and results of any blood tests, including results of genetic tests, current 
medications, information related to your back pain and diagnosis.  
As part of this research study, some information that we obtain from you will be placed into your 
medical records held at UPMC, including the results of safety lab values and other medical tests.
This identifiable medical record information will be made available to members of the research 
team for an indefinite period of time.
Your medical information, as well as information obtained during this research study, may be 
shared with other groups, possibly including authorized officials from the Food and Drug 
Administration, , and the University of Pittsburgh Office of Research Protections, for the purpose 
of monitoring this study. Authorized representatives of UPMC or affiliated health care providers 
may also have access to this information to provide service and addressing billing and 
operational issues.
We will protect your privacy and the confidentiality of your records, as described in this 
document, but cannot guarantee the confidentiality of your research records, including 
information obtained from your medical records, once your personal information is disclosed to 
others outside UPMC or the University.
This authorization is valid for an indefinite period of time.  However, you can always withdraw 
your authorization to allow the research team to review your medical records by contacting the 
investigator listed on the first page and making the request in writing.  If you do so, you will no 
longer be permitted to participate in this study. Any information obtained from you up to that 
point will continue to be used by the research team.
By signing this form, I consent to participate in this research study and provide my authorization 
to share my medical records


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VOLUNTARY PARTICIPATION:
Your participation in this research study is entirely voluntary. You may want to discuss this 
study with your family and friends and your personal physician before agreeing to participate. If 
there are any words you do not understand, feel free to ask us. The investigators will be available 
to answer your current and future questions.
Whether or not you provide your consent for participation in this research study will have no 
effect on your current or future medical care at a UPMC hospital or affiliated health care 
provider or your current or future relationship with a health care insurance provider.
VOLUNTARY CONSENT:
The above information has been explained to me and all of my current questions have been 
answered. I understand that I am encouraged to ask questions, voice concerns or complaints about 
any aspect of this research study during the course of this study, and that such future questions, 
concerns or complaints will be answered by a qualified individual or by the investigator(s) listed 
on the first page of this consent document at the telephone number(s) given..  
I understand that I may always request that my questions, concerns or complaints be addressed by 
a listed investigator. I understand that I may contact the Human Subjects Protection Advocate of 
the IRB Office, University of Pittsburgh (1-866-212-2668) to discuss problems, concerns, and 
questions; obtain information; offer input; or discuss situations that occurred during my 
participation.


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By signing this form I consent to participate in this research study and provide my 
authorization to share my medical records with the research team.   A copy of this consent 
form will be given to me.
Participant’s Signature
Printed Name of Participant
Date
CERTIFICATION of INFORMED CONSENT
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study participation.  
Any questions the individual(s) have about this study have been answered, and we will always be 
available to address future questions as they arise.  I further certify that no research component of 
this protocol was begun until after this consent form was signed.
Printed Name of Person Obtaining Consent
Role in Research Study
Signature of Person Obtaining Consent
Date

Prot_000.pdf: 
Official Title:  Effects of Metformin on Low Back Pain 
ClinicalTrials.gov ID (NCT number): NCT04055012  
Document Date: 05/17/2022 
 
 


Scientiﬁc Background 
Low back pain is one of the most common musculoskeletal conditions requiring medical 
care and contributing to patient impairment and disability, with over 25% of the general 
population reporting low back pain at any given time and a lifetime incidence exceeding 
80%. However, the care of low back pain represents one of the greatest challenges facing 
musculoskeletal care today. Current care for low back pain relies on a trial and error 
approach, with increasingly aggressive options considered after each failed treatment. This 
results in exposure of patients to unnecessary risks associated with treatments that are 
unlikely to be helpful, signiﬁcant wasted resources, and delays in symptom improvement 
(1). In addition, disc degeneration is ubiquitous in our aging population (2-3), in whom 
standard treatments, including injections, surgery, and current medication options 
(particularly NSAIDs and opioids), carry increased risk. With increasing interest in the anti-
aging effects of metformin, and potential effects in the intervertebral disc related to 
inﬂammation, anabolic activity and cell senscence (4), the favorable side effect proﬁle and 
low cost make metformin an attractive therapeutic candidate for the treatment of low back 
pain. In addition, preliminary observational data in patients with low back pain taking 
metformin suggest an improvement in pain score compared to patients not taking 
metformin and over time (see below). With the suggested effects of metformin on the pain 
experience, inﬂammatory cascade (5), and microbiome (6), exploring the associations of 
these key biomarkers with response to oral metformin may reveal sub-populations of 
subjects more likely to respond to treatment as well as novel targets for future therapeutics. 
In addition, because degenerative changes and low back pain increase with age, and aging 
is associated with systemic inﬂammation, older adults may have an even greater response 
to a medication such as metformin, underscoring the potential opportunity of this 
treatment approach. 
We have previously demonstrated associations of protein and genetic biomarkers with pain 
and function in axial low back pain (7-8). In addition, we queried the UPMC data warehouse 
to compare patients with low back pain who were taking metformin vs those taking other 
medications for their diabetes management. Diabetic patients taking metformin (n=26,077) 
had slightly lower average pain scores (6.2) than diabetic patients not taking metformin 
(n=21,540) (6.4). ESR was also lower for patients taking metformin (21.2 vs 26.4). Among 
patients not taking NSAID or oral steroid, average pain scores remained in favor of 
metformin (6.1 vs 6.4). We then queried the database to examine patient pain score one 
year after initial prescription of metformin (n=26,937) and demonstrated small 
improvement in average pain score, from 6.5 to 6.2 after one year of metformin. When these 
patients were limited to patients with an ESR of 10-30 (chosen based on above ﬁnding and 
prior evidence in low back pain (9-10), the average pain score improvement widened to 6.8 
to 6.3. and was similar amongst patients without NSAID or steroid use (6.8 to 6.1). Finally, 
when subjects were further narrowed to patients with ESR 10-20, the pain score changed 
from 9 to 4, however, this resulted in extremely small sample size (n=2). These results justify 
to proposed prospective study (SA1), and also provide evidence of sub-phenotypes of 
patients who will be more likely to respond to treatment (SA2). 
 


In addition to the above data, we have previously developed a clinical prediction model for 
patients with axial low back pain for response to epidural injection. While we accurately 
predicted 22% of the total population with this model, addition of protein and genetic 
polymorphism data into the predictive model as proposed herein improved the predictive 
capacity of the model, demonstrating the feasibility of this approach. 
 
Study Objectives 
The purpose of the current study is to determine the effects of metformin in non-diabetic 
patients with low back pain, and identify novel targets for future treatments. 
Speciﬁc Aim 1: To examine the response in pain and pain related function to oral metformin 
treatment for 6 months in patients with axial low back pain. 
Hypothesis: Patients with axial low back pain treated with metformin for 6 months will 
demonstrate a 2 point or greater improvement in numeric pain rating score and be superior 
to placebo in pain and functional outcome measures. 
Speciﬁc Aim 2: To examine the associations of clinical characteristics, genetic, protein and 
microbiome biologic signatures with response to treatment, and develop a robust 
personalized predictive model for determining response. 
Hypothesis: Polymorphisms in pain perception genes, blood based protein biomarkers, and 
microbiome characteristics will show signiﬁcant associations with response to metformin 
in regard to both pain and pain related function. In addition, older patients with moderate 
levels of systemic inﬂammation will demonstrate a greater response. 
 
Study Design & Methods 
Randomized, placebo controlled, wait list controlled, clinical trial. Subjects will be 
randomized to one of the following groups: 
-High Dose Metformin Group 
-Low Dose Metformin Group 
-High Dose Placebo Group 
-Low Dose Placebo Group 
-Wait-list Control Group (will have a 3 month "wait-list" and then be randomized to 
treatment group at month 3 visit) 
Subjects will take study medication for a total of 6 months 
 
 


Eligibility Criteria 
Inclusion criteria: 
-Age 18 and above 
-Diagnosed with axial low back pain (low back pain more severe than pain in other parts of 
the body, without radiation of pain into the lower extremities). 
-Women of child bearing potential must have a negative serum pregnancy test at baseline. 
Exclusion criteria: 
-Diagnosed with rheumatoid arthritis, lupus, other autoimmune/systemic inﬂammatory 
arthropathies 
-Progressive lower extremity weakness or numbness 
-Recent oral or injected steroid use (within last 3 months) 
-NSAID use 
-Chronic kidney disease (eGFR <60) 
-Diagnosis of diabetes mellitus or elevated HbA1c at screening (> 6.5) 
-Subjects must not be pregnant or breastfeeding, or planning to become pregnant or 
breastfeed during the course of the trial 
-Unable to take an oral medication in a non crushable pill form 
-Taking metformin presently or within the last 6 months 
-History of allergy to metformin 
-History of lactic acidosis or elevated lactate at screening (> 2.2) 
-Severe Hepatic dysfunction 
-Currently taking a diabetic medication such as sitagliptin, saxagliptin, linagliptin, 
alogliptin, sitagliptin with metformin 
-Currently taking a Carbonic anhydrase inhibitor such as topiramate, zonisamide, 
acetazolamide, dichlorphenamide, methazolamide 
-Currently taking cimetidine 
 
Statistical Considerations 
Sample size is estimated based on feasibility of subject recruitment based on prior study of 
axial low back pain, as well as prior studies demonstrating clinically and statistically 
signiﬁcant change in the primary outcome of NPRS for randomized trials of NSAID in as few 
as 37-295 patients. For patients who met all inclusion criteria in our previous study 


examining epidural steroid injection for axial low back pain, our successful recruitment rate 
was 72%. For this prior study, we screened 1455 subjects over a one year period, and 768 
were excluded due to leg pain/radiculopathy. Therefore, we expect adequate availability of 
subjects to meet our recruitment goal. Formal sample size justiﬁcation based on 80% 
power, alpha = 0.05: 
Effect Sizes: 
High vs. Low: 0.79 
High vs. placebo: 0.79 
Low vs. placebo: 0.79 
Control vs. placebo: 0.86 
*These are all based on two-sample t-tests with a common variance. 
Per MOD19010007-009: While we retained data from the initial enrollment, they not be 
included in the parent statistical analysis. Therefore, this would not impact the overall 
analysis plan since re-enrolled patients would complete the new proposed baseline data 
collection (ie treated as an entirely new subject). 
Since there has been sufficient wash-out period for medication and the short time enrolled 
in the study, re-enrolling subjects is not expected to inﬂuence results 
 
 

SAP_001.pdf: 
Official Title:  Effects of Metformin on Low Back Pain 
ClinicalTrials.gov ID (NCT number): NCT04055012  
Document Date: 12/11/2024 
 
 
 
 


Statistical Analysis Plan 
The primary outcome is change in pain score and disability score between baseline and 12 
months, using the minimal clinically meaningful change.  Sample size was estimated based 
on feasibility of subject recruitment based on prior study of axial low back pain, as well as 
prior studies demonstrating clinically and statistically signiﬁcant change in the primary 
outcome of NPRS. However, given the early termination of the study prior to reaching an 
adequate sample size, outcome measures are reported with descriptive statistics only, ie. 
mean and standard deviation, with insufficient numbers to permit formal between group 
comparisons.