Graves’ disease Nutritional, Metabolic, Endocrine Graves’ disease
Conditions
Interventions
Stage 1 is a dose-response study using 4 doses of daratumumab (9 mg/kg, 3 mg/kg, 1 mg/kg, 0.5 mg/kg) and a colourless, volume-matched placebo infusion in approximately 15 patients (i.e. five groups of
Sponsors
Newcastle upon Tyne Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 23/02/2024: 1. Patients =18 years old 2. Recent-onset Graves’ disease (within 12 months) (defined as the date of first thyroid function test showing hyperthyroidism (FT4 and TSH) in the current episode) 3. TRAb antibody concentrations above 10 U/L (on Roche or Brahms TBII assays) 4. One or more of: 4.1. Pre-treatment severe hyperthyroidism (FT4 =50 pmol/L; or FT3 =15 pmol/l) 4.2. Persisting hyperthyroidism despite more than 12 weeks of antithyroid drug therapy (defined as FT3 above the upper limit of the reference range following 12 weeks of carbimazole treatment at a dose of 40mg or more daily (or equivalent dose of PTU)) 4.3. Inflammatory thyroid eye disease (defined as clinical activity score, CAS =3), or thyroid dermopathy 4.4. Large (visible) goitre (WHO grade III) 4.5 2 or more relapses (3 episodes in total) despite completing 12 months or more of medical treatment on each occasion. Relapse is defined as FT3 above the upper limit of the local reference range. 5. For women of childbearing potential, willing to use a highly effective contraceptive method during their participation in the trial. 6. Able to understand and speak sufficient English to complete trial procedures 7. Willing and able to provide informed consent prior to any trial procedures taking place _____ Previous inclusion criteria: 1. Patients =18 years old 2. Recent-onset Graves’ disease (within 12 months) (defined as the date of first thyroid function test showing hyperthyroidism (FT4 and TSH)) 3. TRAb antibody concentrations above 10 U/L (on Roche or Brahms TBII assays) 4. One or more of: 4.1. Pre-treatment severe hyperthyroidism (FT4 =50 pmol/L; or FT3 =15 pmol/l) 4.2. Persisting hyperthyroidism despite more than 12 weeks of antithyroid drug therapy (defined as FT3 above the upper limit of the reference range following 12 weeks of carbimazole treatment at a dose of 40 mg or more daily (or equivalent dose of PTU)) 4.3. Inflammatory thyroid eye disease (defined as clinical activity score, CAS = 3), or thyroid dermopathy 4.4. Large (visible) goitre (WHO grade III) 5. For women of childbearing potential, willing to use a highly effective contraceptive method during their participation in the trial. 6. Able to understand and speak sufficient English to complete trial procedures 7. Willing and able to provide informed consent prior to any trial procedures taking place
Exclusion criteria
Exclusion criteria: 1. Previous thyroidectomy, or radioiodine treatment within 2 years 2. Pregnant or breastfeeding, or with a plan for pregnancy within 6 months 3. Previous shingles, known untreated cervical dysplasia, hepatitis B & C, or HIV infection 4. Anaemia (Hb =100g/l),thrombocytopenia (=75 x10^9/L) or neutropenia (=1.0 x10^9/L) 5. Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma without hospitalisation is allowed) 6. Any other significant physical or mental health conditions, e.g. major cardiorespiratory disease, renal or hepatic failure, pancreatitis, cancer undergoing active treatment (excluding non-melanoma skin cancer), untreated chronic infection including TB, psychosis, depression impairing Activities of Daily Living 7. Current use of immunosuppressive therapy for thyroid eye disease or other conditions (within 3 months) 8. Current or previous participation in a CTIMP research study within 4 months 9. Hypersensitivity or anaphylactic reaction to previous monoclonal antibody treatments or methylprednisolone 10. Inability, in the opinion of the investigator, to be able to complete the clinical trial visits or procedures.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Serum TRAb antibodies measured using blood samples at baseline and 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Serum TRAb antibodies measured using blood samples at baseline and 2, 4, 6, 12 and 24 weeks 2. Dose-response curve for daratumumab against serum TRAb antibodies measured using blood samples at baseline and 6 and 12 weeks 3. Serum FT3 & FT4 measured using blood samples at baseline and 2, 4, 6, 12 and 24 weeks 4. Serum TSH measured using blood samples at baseline and 2, 4, 6, 12 and 24 weeks 5. Thyroid volume measured by ultrasound at baseline and 24 weeks 6. Serum ATPO and thyroglobulin antibodies measured using blood samples at baseline and 6, 12 and 24 weeks 7. CAS, composite eye index and GOQoL score measured using an eye exam and a patient completed questionnaire at baseline and 6, 12 and 24 weeks 8. ThyPRO39 score measured using a patient completed questionnaire at baseline and 6, 12 and 24 weeks 9. Serum immunoglobulins, specific antibodies including (SARS-CoV2) and blood count parameters measured using blood samples from baseline and 6, 12 and 24 weeks 10. Adverse Reactions to 24 weeks measured using patient and clinician reported adverse events Exploratory outcome measures 1. Analysis of blood plasma cell markers and mRNA signature measured using blood samples at baseline and 6, 12 and 24 weeks 2. Lymphocyte subsets (by FACS) measured using blood samples at baseline and 6, 12 and 24 weeks | — |
Countries
England, United Kingdom
Outcome results
None listed