Tirzepatide Monotherapy in Patients With Wolfram Syndrome Type 1

February 21, 2024 updated by: Lorenzo Piemonti, Ospedale San Raffaele

Towards a Personalized Precision Medicine in Rare Disease: Tirzepatide (a Dual Glucose-dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 Receptor Agonist) Monotherapy in Patients With Wolfram Syndrome Type 1

Wolfram syndrome (WFS:OMIM 222300) is a group of inherited disorders that usually appear in childhood and cause diabetes, optic atrophy leading to loss of vision, deafness and often diabetes insipidus. Wolfram syndrome affected no more than 0.2 in 10,000 people in the European Union. There is no cure and no treatment that will arrest or delay the progress of the disease.

The gene responsible for WS1 is WFS1, it encodes for wolframin, a transmembrane glycoprotein involved in the regulation of the unfolded protein response. Recently, drug repurposing has been hypothesized from others and us as being useful for WS1 therapy. More specifically, GLP-1 receptor agonists were suggested as a promising class of anti- diabetic drugs having the potential to delay or even reverse disease progression based on their ability to reduce elevated ER stress in vitro and in vivo.

The objective of this project is to create a model of precision-medicine oriented Rare Diabetes Clinic, which will be specifically dedicated to the treatment and follow-up of complex patients with Wolfram Syndrome. A team of clinicians and researchers specialized in diabetes and/or optic neuropathy and with experience in the subset of monogenic forms will make available a cohort of subjects with Wolfram Syndrome prospectively followed in an interventional protocol on the use of tirzepatide (a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist). It will be a prospective phase 2, non-randomized, single group assignment, intervention trial to determine the efficacy of tirzepatide (GIP/GLP-1 receptor agonist) in increasing endogenous insulin production and correcting glycemic lability in patients with Wolfram syndrome type 1 (WS1).

The expected outcomes of this study are 1) to provide a therapeutic option for a devastating orphan disease; 2) to confirm the efficacy of a repurposed drug able to reduce elevated endoplasmic reticulum (ER) stress in a disease that represents a model of ER disease; 3) to confirm the efficacy of the disease modeling based on iPSC to predict the response to treatment; 4) to develop a disease-specific multidisciplinary follow-up.

Study Overview




Intervention / Treatment

Study Type


Enrollment (Estimated)



  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

      • Milan, Italy, 20132
        • Recruiting
        • IRCCS San Raffaele Scientific Institute
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Amelia Carretto, MD
        • Principal Investigator:
          • Giulio Frontino, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers



Inclusion Criteria:

  1. A definitive diagnosis of Wolfram syndrome, as determined by the following:

    1. Documented diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria AND
    2. Documented functionally relevant recessive mutations on both alleles of the WFS1 gene or dominant mutation on one allele of the WFS1 gene based on historical test results (if available) or from a qualified laboratory at screening;
  2. Aged 5 years or older;
  3. The patient, patient's parent(s), or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient. The guardians' consent and patient's assent, as relevant, must be obtained;
  4. Females of child bearing potential will only be included after a negative highly sensitive urine pregnancy test. If sexually active, they must agree to use a highly effective contraception measure;
  5. Patient willing to wear a continuous glucose monitor.

Exclusion Criteria:

  1. Clinically significant non-Wolfram related CNS involvement which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments;
  2. A history of pancreatitis;
  3. Pre-existing thyroid disease;
  4. A personal or family history of medullary thyroid carcinoma;
  5. Multiple Endocrine Neoplasia syndrome type 2;
  6. Active liver or renal disease, personal or family history of liver/kidney dysfunction related to known genetic disorders;
  7. Treatment with any investigational drug within the 30 days prior to Trial entry;
  8. Current therapy with of GLP-1 agonist or DDP-4 inhibitor or a known hypersensitivity to GLP-1 agonist;
  9. Any other acute or chronic medical, psychiatric, social situation or laboratory result that, based on investigator's judgment, would jeopardize patient safety during trial participation, cause inability to comply with the protocol, or affect the Trial outcome;
  10. Breastfeeding;
  11. Pre-existing ocular disease (corneal or lens diseases and any other retinal or optic nerve non-Wolfram related diseases).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Interventional group
Tirzepatide will be injected subcutaneously once-per-week, in the abdomen, thigh or upper arm. To improve gastro-intestinal tolerability, the starting dose will be 5 mg (2.5mg for prepubertal children) and will be increased to a maximum of 15 mg (or highest tolerated dose).
tirzepatide once weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
changing in endogenous insulin production
Time Frame: [Time Frame: month 6±1, month 12±1]
C-peptide response in the Mixed Meal Tolerance Test (MMTT; change from baseline C-peptide response)
[Time Frame: month 6±1, month 12±1]
changing in insulin production
Time Frame: [Time Frame: month 6±1, month 12±1]
mean change from baseline in stimulated 2 hour plasma C-peptide AUC (from MMTT) maximum stimulated plasma C-peptide: the highest value at any time point during the MMTT
[Time Frame: month 6±1, month 12±1]

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
glucose variability
Time Frame: [Time Frame: month 6±1, month 12±1]
change from baseline in average glucose (measured by continuous glucose monitoring)
[Time Frame: month 6±1, month 12±1]
glycemic variability
Time Frame: [Time Frame: month 6±1, month 12±1]
change from baseline in coefficient of glucose variation (measured by continuous glucose monitoring)
[Time Frame: month 6±1, month 12±1]
change in time in range
Time Frame: [Time Frame: month 6±1, month 12±1]
change from baseline in time in range (measured by continuous glucose monitoring)
[Time Frame: month 6±1, month 12±1]
change in insulin requirements
Time Frame: [Time Frame: month 3±1, month 6±1, month 12±1]
change from baseline in mean daily insulin use over the 3 days preceeding the study visits. The mean daily insulin use value will be calculated, in units of U/kg/day, as the mean of the values of amount of insulin used per day on each of the last three consecutive days preceeding each study visits.
[Time Frame: month 3±1, month 6±1, month 12±1]
change in HbA1c
Time Frame: [Time Frame: month 3±1, month 6±1, month 12±1]
change from baseline in HbA1c
[Time Frame: month 3±1, month 6±1, month 12±1]

Collaborators and Investigators

This is where you will find people and organizations involved with this study.


  • Principal Investigator: Lorenzo Piemonti, MD, Ospedale San Raffaele

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2024

Primary Completion (Estimated)

October 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

December 5, 2022

First Submitted That Met QC Criteria

December 12, 2022

First Posted (Actual)

December 21, 2022

Study Record Updates

Last Update Posted (Estimated)

February 22, 2024

Last Update Submitted That Met QC Criteria

February 21, 2024

Last Verified

February 1, 2024

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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