Design
The HIGHT trial (Herbs of rich-iodine for Graves’ Hyperthyroidism Trial) is a randomized, double-blind, placebo-controlled and multicentre clinical trial in patients with Graves' hyperthyroidism who have any common ATD-associated side-effects. The trial has a multi-arm design with 1:1:1 allocation to the experimental intervention group (A group), the control intervention group (B group) and combined intervention group (C group), and involving five clinical trial centers in China (The affiliated hospital of Liaoning Traditional Chinese Medicine University, Xinjiang Uygur Autonomous Region Hospital of Traditional Chinese Medicine, The affiliated Shuguang hospital of Shanghai Traditional Chinese Medicine University, Liaoning Armed Police Corps Hospital, The 2nd affiliated hospital of Liaoning Traditional Chinese Medicine University). Figure 1 briefly shows the study flow chart, and the time-point of assessment is shown in Table 1. The development of the protocol of this study is per Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guideline.[27]
Table 1
SPIRIT schedule for enrollment, treatment, and assessments
Item | Enrolment/Baseline | Intervention period |
| -within 1 week | Week 2 | Week 4 | Week 8 | Week 12 |
Visit | 1 | 2 | 3 | 4 | 5 |
Informed consent | × | | | | |
Demographic information | × | | | | |
Record of medical history | × | | | | |
General physical examination | × | × | × | × | × |
ThyPRO39 | × | × | × | × | × |
Pregnancy Test | × | | | | × |
FT3, FT4, TSH | × | × | × | × | × |
TRAb | × | × | × | × | × |
TgAb, TPOAb | × | × | × | × | × |
Serum iodine | × | | | | × |
Iodine /creatinine ratio in spot urine | × | | | | × |
Thyroid Ultrasound (US.) | × | | × | | × |
Blood and urine regulation* | × | × | × | × | × |
ALT, AST,TBIL,ALP,γ-GT* | × | × | × | × | × |
BUN, Cr, K, Ca | × | × | × | × | × |
Electrocardiogram | × | × | × | × | × |
Selection/exclusion criteria | × | | | | |
Drugs of prohibition | × | × | × | × | × |
Drug Distribution and record | × | | × | × | |
Drug combination | × | × | × | × | × |
Adverse reactions/Adverse events | ×# | × | × | × | × |
Referral to ablative therapy## | | × | × | × | × |
All assessments must be made at the time points specified above. If the assessment is not possible at the specified time, the assessment shall still be conducted, and the time shall be noted in the electronic case report form (eCRF). Following this, deviations from the protocol can be assessed. ThyPRO39: Thyroid-specific Patient Reported Outcome; FT3: free triiodothyronine; FT4: free thyroxine; TSH: levels and serum thyroid-stimulating hormone; TRAb: TSH-receptor Antibody; TPOAb: Thyroid peroxidase antibody; US: Ultrasound; TgAb: Thyroglobulin antibody. *Patients should be informed of potential side effects of ATD and the necessity of informing the physician promptly if they should develop jaundice, light-colored stools, dark urine, fever, pharyngitis, or cystitis. In patients taking ATD, a differential white blood cell count should be obtained during febrile illness and/or pharyngitis, and liver function should be assessed in those who experience jaundice, light-colored stools, or dark urine. Full Blood Count every week for 4 weeks and then every 4 weeks; Liver Function Tests (LFT) every 2 weeks for 4 weeks and then every 4 weeks. # Adverse reactions of former treatment of ATD. ##That is, thyroid surgery or RAI therapy. |
Figure 1 Trial flow chart
Table 1 SPIRIT schedule for enrollment, treatment, and assessments
Sample size
According to the previous studies, we assumed an effective rate would be 90%. The sample was estimated according to the parameters: a significance level of 5%, power of 80%.
n = 2π(1-π) (µα + U1−β/2) 2/ δ2 = 66.355
Thus, the sample size was 80 subjects in each group with drop-out rate of 20%. A total of 240 subjects will be recruited and divided into three groups of 80 subjects each.
Intervention
Study recruits receive respectively IRH plus placebo MMI (A group), placebo IRH plus MMI (B group), or IRH plus MMI (C group). Participants in three groups will take either IRH or the placebo IRH twice daily (10 g/packet at a time), plus either MMI or placebo MMI once daily (5–10 mg at a time) for 12 weeks. The drugs will be distributed to Graves' hyperthyroidism patients per month.
Both IRH and placebo granules are manufactured by Jingyin Pharmaceutical (Jingyin, China) according to good manufacturing practice guidelines. Drugs will be prepared in the form of brown granules. The constituents of IRH are kelp, spica prunellae, oldenlandia, and so on. The placebo will consist of corn starch, lactose hydrate, citric acid, and caramel color. The placebo and IRH will have the same size, appearance, smell and taste. They are packaged in the same packet, labelled as trial-specific Investigational Medicinal Products (IMPs) as the IRH granules, and then distributed to the 5 centres.
MMI tablets (Thyrozol, 10mg × 50) are produced by Merck KGaA, Germany. The placebo MMI tablets are made for the trial by Beijing Chengyou Pharmacy Manufacturing Unit in accordance with good manufacturing practice and exactly match the size, appearance, taste, smell of the active MMI tablets, which are removed from their blister-packs and re-packaged in the same bottles as the placebos. Both active and placebo drugs are then labeled as trial-specific IMPs and distributed to the 5 centres.
Randomization and allocation concealment
Randomization using Statistics Analysis System (SAS) software will be performed by independent staff statisticians. Participants will be randomly assigned to either the A or B or C group in a 1:1:1 ratio. The study coordinator will be blinded to the group assignment and will give participants the numbered package of intervention according to their visiting time sequence at baseline visit. Thus, the allocation concealment will be maintained throughout the study. The allocation for each subject will be sealed in an opaque envelope and will not be disclosed until the clinical trial is completely over, unless serious adverse events (SAEs) happen.
Blindness
Double-blinding method is adopted in this study. Both participants and investigators will be blinded to the allocation until completion of the trial. The each placebo drug was confirmed in advance that the size, appearance, taste and flavor were similar. According to the randomization sequence, drugs will be packed in the same form and will be delivered to the hospital. At the end of the study, the blinding codes will be revealed. In case of SAEs, an administrator will unblind the patient information as an emergency and provide relevant treatment.
Concomitant medication or treatment
The use of any traditional medicine designed to treat Graves' hyperthyroidism, except for the intervention of this trial, will be prohibited during the study. During the treatment, the clinician can decide whether to combine with β-adrenergic blocker, antihistamine agents, hepatoprotective agents and leukocytopoiesis-promoting agents according to the specific condition. All concomitant medication and treatment (that is, treatment drugs / treatment measures for other diseases) during the study period will be recorded in the combined medication table in detail.
Discontinuation
Participants may withdraw from the trial at any time for any reason, and the reason will be recorded in the electronic case report forms (eCRFs). In order to conduct intention-to-treat analyses with as few missing data as possible, the investigator may ask the participants which aspects of the trial, they wish to withdraw from.These can include the following: receipt of the trial intervention, participation in the remaining follow-up assessments, or use of already collected data in the data analyses. The investigators will discontinue a participant’s taking of the trial intervention at any time, if the participant: experiences intolerable adverse reactions; is diagnosed with any of the exclusion criteria during the intervention period; is referred for ablative therapy (RAI or thyroid surgery) during the intervention period. In all three cases, the investigator and/or the treating physician will encourage the participant to continue with follow up assessment and to allow the use of collected data in the analyses.
Safety assessment
Safety will be assessed in terms of the routine physical examination consists of breath rate, heart rate, temperature, blood pressure, weight, and routine kidney function, liver function, blood, urine, and electrocardiogram test results obtained at 2, 4, 8 and 12 weeks of treatment, respectively. Adverse events, vital signs, and laboratory examinations will be recorded on eCRFs before and after patients take their medication at every visit. Adverse events (AEs) are defined as any unexpected sign or symptom during the treatment period, and participants will be asked to inform clinicians about the occurrence of any AEs while taking their medication. The researchers will then comprehensively evaluate the relation between these AEs and the experimental drugs according to the records, including the occurrence time, duration, manifestation, cause, and treatment measures. If SAEs occur that may lead to death or require extended hospitalization, the participants will be asked to quit the clinical trial as soon as possible, and proper treatment will be provided.
Data management and Monitoring
All researchers involved in the study will be qualified physicians. All source documents, such as informed consent forms, signature of participants and questionnaires, will be collected and conserved in compliance with standard operating procedures (SOP). The data will be collected via an electronic data capture system through eCRFs using the OpenClinical EDC management system. The main data will be locked up until research completed. For the questions in the eCRFs, data manager should inquire the researchers through clinical supervisor and make data modification, affirmation and record according to the reply of researchers. The principal investigator will coordinate dissemination of data.
The administrators of the Affiliated Hospital of Liaoning Traditional Chinese Medicine University will visit each unit regularly (once a month) to confirm the quality of data collection and facilitate problem-solving and the Ethics Committee will monitor for protocol violations. The safety, progress, study integrity, and design aspects will be monitored by the research team involved in this study.