Diabetes Mellitus, Type 1ADDAMNCT03988764
Monogenic Diabetes Misdiagnosed as Type 1
An observational study of Diabetes Mellitus, Type 1 and Monogenic Diabetes, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 1 site in Canada.
Trial summary
The study has two aims: 1. To (1a) determine the frequency of monogenic diabetes misdiagnosed as type 1 diabetes (T1D) and (2) to define an algorithm for case selection. 2. To discover novel genes whose mutations cause monogenic diabetes misdiagnosed as T1D. Read more about this study
- Who is it for?
- Ages 1 day to 25 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Type 1, Monogenic Diabetes, Neonatal Diabetes
- What is being tested?
- None AHT
- How many people
- 5,000 participants
- Where
- 1 siteCanada
- Study dates
- 24 Sep 2019to 31 Dec 2025
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 25 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: Cases diagnosed as type 1 diabetes or undetermined type.
Who may be able to join
- Diagnosis of diabetes under the age of 25 as either type 1 or undetermined type.
Who cannot join
- Existing T1D autoantibody testing with a positive result
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
The Montreal Children's Hospital
Montreal, Quebec, H4A 3J1
Natalija Popovic, PhD, 514-934-1934 ext. 22623, natalija.popovic@muhc.mcgill.ca
Angeliki Makri, MD, 514-934-1934 ext. 22623, angeliki.makri@mcgill.ca
About this study
Official title: Accurate Diagnosis of Diabetes for Appropriate Management
The study has two aims:
- To (1a) determine the frequency of monogenic diabetes misdiagnosed as type 1 diabetes (T1D) and (2) to define an algorithm for case selection.
- To discover novel genes whose mutations cause monogenic diabetes misdiagnosed as T1D.
Read the detailed description
Aim 1. The investigators will recruit 5,000 cases diagnosed as T1D under the age of 25, from 17 participating clinics across Canada. All cases will be tested for four antibodies (against proinsulin, GAD65, islet antigen 2 (IA-2), and ZnT8). Cases negative for all four will be exome-sequenced.
- Variant annotation will be focused on known monogenic diabetes genes. Variants rated as pathogenic, likely pathogenic or of unknown significance whose zygosity fits the genetic model, will be confirmed in a clinically certified laboratory and communicated to the treating health care team. End-point is the frequency of such variants compared to their frequency in control, non-T1D exomes.
- The following variables will be examined for the ability to predict monogenic diabetes: Negativity for all autoantibodies tested, family history, polygenic T1D risk score, age of onset, sex, glycosylated hemoglobin (HbA1c), insulin dose, and presence of syndromic features. Predictors will be analyzed by multiple regression and results subjected to jackknife (leave-one-out) validation. Machine-learning techniques may be used.
Aim 2. Variants outside known genes in non-diagnostic exomes will be annotated and examined under autosomal dominant, recessive, X-linked and mitochondrial inheritance models. Corresponding frequency cutoffs will be 0.0005, 0.01, 0.001 and 0.0005 (if heteroplasmy >70%). Formal mutation-burden analysis will be based on depth-adjusted data from the Genome Aggregation Database (gnomAD). Genes mutated in more than one unrelated proband will be examined by a statistical approach taking into account the presence of a large number of phenocopies (Akawi et al., Nat Genet. 2015;47:1363-1369). Genes that achieve statistical significance will be tested in additional cohorts with international collaborations.
- Conditions
- Diabetes Mellitus, Type 1, Monogenic Diabetes, Neonatal Diabetes, Maturity-onset Diabetes in the Young (MODY), Wolfram Syndrome, Wolcott-Rallison Syndrome
- Being tested
- None AHT
- Medical subject headings
- Diabetes Mellitus, Type 1, Wolfram Syndrome, Wolcott-Rallison syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
None AHTOther
No further intervention planned for either group as part of the current study.
| Study group | Role | What they receive |
|---|---|---|
| Antibody-negative | Patient has been found negative for at least three T1D antibodies.
The investigators will proceed with whole exome sequencing Receives: Other: None AHT | |
| Antibody-positive | Patient has been found to be positive for at least one T1D autoantibody.
No further studies will be performed as part of the main study. Receives: Other: None AHT |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of monogenic diabetes among patients diagnosed as type 1 diabetes.
The exomes of all patients negative for four T1D autoantibodies will be sequenced and pathogenic variants in genes known to cause monogenic diabetes will be called and annotated. The frequency of genes carrying such variants among these patients will be compared to control exomes from public databases.
Measured: 6 years
Proportion of patients carrying mutations in previously unstudied genes that meet statistical criteria of pathogenicity for monogenic diabetes.
Exomes not found to carry a mutation (per outcome 1) will be analyzed to discover pathogenic variants in novel genes. Genes mutated in more than one unrelated probands will be statistically evaluated to see if variants in these gene occur more frequently than in control exomes. The number of probands that is needed to fulfill this criterion will depend on the gene's tolerance to protein-altering mutations.
Measured: 7 years
Secondary outcomes (1)
Risk-prediction score for monogenic diabetes mutation in antibody negative T1D patients
Composit score with a statistically significant ROC curve for predicting monogenic diabetes in individuals previously diagnosed as T1D. It will be based on age of onset, T1D polygenic risk score. The risk score will aim to predict monogenic diabetes in cases with clinical T1D diagnosis and known to be antibody negative. The scale will be calculated as follows: From the exome sequencing, the investigators will be able to determine genotype at the three most important loci determining risk for autoimmune T1D (HLA, INS and PTPN22).The composite risk score, along with family history, age of onset, HbA1c+4*insulin dose/kg (as proxy for residual beta cell function) will be subjected to logistic regression for an overall risk. The ROC curve will be used to select a point likely to capture most cases unlikely to have autoimmune T1D, sacrificing specificity to maximize sensitivity. Data will be validated with jackknife cross-validation.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jun 2019
- Study start24 Sep 2019
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 1Studies of the same condition, open and under way.
- More trials run by McGill University Health Centre/Research Institute of the McGill University Health CentreThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 5,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Constantin Polychronakos, McGill University Health Centre/Research Institute of the McGill University Health Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03988764
- Sponsor's protocol ID
- ADDAM
- Other IDs
- Canscreen
- Acronym
- ADDAM
- Status last verified
- Dec 2024
- First submitted
- 11 Jun 2019
- Last updated
- 10 Dec 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Anonymized exome data will be deposited in publicly available databases.15
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Accurate Diagnosis of Diabetes for Appropriate Management
- ClinicalTrials.gov ID
- NCT03988764
- Acronym / sponsor ID
- ADDAM / ADDAM
- Conditions
- Diabetes Mellitus, Type 1, Monogenic Diabetes, Neonatal Diabetes, Maturity-onset Diabetes in the Young (MODY), Wolfram Syndrome, Wolcott-Rallison Syndrome
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 5,000 participants (estimated)
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health CentreUniversity, hospital or other
- Study start
- 24 Sep 2019 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 17 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study has two aims:
- To (1a) determine the frequency of monogenic diabetes misdiagnosed as type 1 diabetes (T1D) and (2) to define an algorithm for case selection.
- To discover novel genes whose mutations cause monogenic diabetes misdiagnosed as T1D.
Detailed description
Aim 1. The investigators will recruit 5,000 cases diagnosed as T1D under the age of 25, from 17 participating clinics across Canada. All cases will be tested for four antibodies (against proinsulin, GAD65, islet antigen 2 (IA-2), and ZnT8). Cases negative for all four will be exome-sequenced.
- Variant annotation will be focused on known monogenic diabetes genes. Variants rated as pathogenic, likely pathogenic or of unknown significance whose zygosity fits the genetic model, will be confirmed in a clinically certified laboratory and communicated to the treating health care team. End-point is the frequency of such variants compared to their frequency in control, non-T1D exomes.
- The following variables will be examined for the ability to predict monogenic diabetes: Negativity for all autoantibodies tested, family history, polygenic T1D risk score, age of onset, sex, glycosylated hemoglobin (HbA1c), insulin dose, and presence of syndromic features. Predictors will be analyzed by multiple regression and results subjected to jackknife (leave-one-out) validation. Machine-learning techniques may be used.
Aim 2. Variants outside known genes in non-diagnostic exomes will be annotated and examined under autosomal dominant, recessive, X-linked and mitochondrial inheritance models. Corresponding frequency cutoffs will be 0.0005, 0.01, 0.001 and 0.0005 (if heteroplasmy >70%). Formal mutation-burden analysis will be based on depth-adjusted data from the Genome Aggregation Database (gnomAD). Genes mutated in more than one unrelated proband will be examined by a statistical approach taking into account the presence of a large number of phenocopies (Akawi et al., Nat Genet. 2015;47:1363-1369). Genes that achieve statistical significance will be tested in additional cohorts with international collaborations.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Antibody-negative | – | Other: None AHTPatient has been found negative for at least three T1D antibodies. The investigators will proceed with whole exome sequencing |
| Antibody-positive | – | Other: None AHTPatient has been found to be positive for at least one T1D autoantibody. No further studies will be performed as part of the main study. |
Who may qualify
- Ages
- 1 day to 25 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- Cases diagnosed as type 1 diabetes or undetermined type.
Key inclusion criteria (1 listed)
- Diagnosis of diabetes under the age of 25 as either type 1 or undetermined type.
Key exclusion criteria (1 listed)
- Existing T1D autoantibody testing with a positive result
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| None AHTNo further intervention planned for either group as part of the current study. | Other | Antibody-negative, Antibody-positive |
Primary outcome
Proportion of monogenic diabetes among patients diagnosed as type 1 diabetes.
Time frame: 6 years
The exomes of all patients negative for four T1D autoantibodies will be sequenced and pathogenic variants in genes known to cause monogenic diabetes will be called and annotated. The frequency of genes carrying such variants among these patients will be compared to control exomes from public databases.
Proportion of patients carrying mutations in previously unstudied genes that meet statistical criteria of pathogenicity for monogenic diabetes.
Time frame: 7 years
Exomes not found to carry a mutation (per outcome 1) will be analyzed to discover pathogenic variants in novel genes. Genes mutated in more than one unrelated probands will be statistically evaluated to see if variants in these gene occur more frequently than in control exomes. The number of probands that is needed to fulfill this criterion will depend on the gene's tolerance to protein-altering mutations.
1 secondary outcome
Risk-prediction score for monogenic diabetes mutation in antibody negative T1D patients
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2024.
- Individual participant dataSharing planned: Yes. Anonymized exome data will be deposited in publicly available databases.15
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Diabetes Mellitus, Type 1 and Monogenic Diabetes, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 10 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Constantin Polychronakos, MD (5144124400 ext. 22866, constantin.polychronakos@mcgill.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of monogenic diabetes among patients diagnosed as type 1 diabetes. (time frame: 6 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2024.