Decreasing Risk of Psychosis by Sulforaphane (DROPS Trial)

Clinical High Risk Syndrome of Psychosis Clinical Trial

Official title:

Decreasing Risk of Psychosis by Sulforaphane: Study Protocol for a Randomized, Double-blind, Placebo-controlled, Clinical Multicenter Trial (DROPS Trial)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03932136
• Other study ID #: 03
• Status: Recruiting
• Phase: Phase 3
• Start date: July 14, 2019
• Est. completion date: December 31, 2026

Study information

• Verified date: October 2023
• Source: Shanghai Jiao Tong University School of Medicine
• Contact: Jijun Wang, PhD
• Phone: +8618616572179
• Email: jijunwang27[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double-blind, placebo-controlled, multi-centre trial. A total of 300 CHR subjects will be identified in the course of face-to-face interviews using the Structured Interview for Prodromal Syndromes. All participants will be randomly allocated to SFN group (n = 150) or placebo group (n = 150). The study duration includes an intervention for 52 consecutive weeks, and additional 1-year follow-up. The primary outcome is 2-year conversion rate of psychosis. Secondary outcomes include 1-year conversion rate of psychosis, the severity and duration of prodromal symptoms, predictive risk of psychosis conversion, neurocognitive functioning and peripheral blood biomarkers of inflammation, oxidative stress and metabolism. Safety monitoring will be performed using scales for side effect, serious adverse events recording, and laboratory tests.

Description:

Study design: This study is designed as a randomized, double-blind, placebo-controlled, clinical multi-centre trial. Its main objective is to evaluate the efficacy of SFN vs placebo in decreasing risk and conversion rate of psychosis in CHR population. A total of 300 CHR subjects will be recruited at eight research centres. All participants will be provided withan explanation about the study, and informed consent will be obtained from each participant before participation. The study duration includes an intervention with SFN or placebo for 52 consecutive weeks, and additional 1-year follow-up. The primary outcome is conversion rate of psychosis at the end of follow-up (104 weeks). The secondary outcomes mainly include conversion rate of psychosis at the end of intervention (52 weeks), the severity and the duration of prodromal symptoms, predictive risk of psychosis conversion, neurocognitive functioning and biomarkers of inflammation, oxidative stress and metabolism in peripheral blood. Safety outcomes include side-effects, serious adverse events, laboratory tests, which will be obtained from all participants.

Setting:This study involves eight research centres in China include Shanghai Mental Health Center, Shanghai Xuhui District Mental Health Center, Shanghai Pudong Nanhui Mental Health Center, Suzhou Guangji Hospital, Second Xiangya Hospital of Central South University, Guangzhou Huiai Hospital, Tianjin Anding Hospital, and the First Affiliated Hospital of Zhengzhou University. Shanghai Mental Health Center is the leading centre. Before the trial, standardized training in interview and rating will be provided to all centres equally.

CHR identification: CHR subjects will be identified in the course of face-to-face interviews using the structured interview for prodromal syndromes (SIPS) (Miller et al., 2002; Miller et al., 2003). CHR subjects meet the criteria of prodromal syndromes (COPS) for the attenuated positive symptom syndrome (APSS), brief intermittent psychotic syndrome (BIPS), or genetic risk and deterioration syndrome (GRDS) according to the SIPS. CHR diagnosis will be made by a panel of senior psychiatrists. Severity of CHR subjects' prodromal symptoms will be assessed using the scale of prodromal symptoms (SOPS) (Miller et al., 1999) based on SIPS. In addition, the Positive and Negative Syndrome Scale (PANSS) will be used for rating the severity of psychotic symptoms.

Inclusion criteria:The inclusion criteria of this study are as follows: (a) Subjects meet the criteria of CHR according to SIPS; (b) Subjects will have no history of being medicated with either antipsychotics or mood stabilizers at their first study visit; (c) Age, within the range of 15 to 45 years; (d) Patients and/or their legal guardians for those younger than 18 year old, can understand and sign informed consent, and agree to take the study interventions and complete all visits and examinations.

Exclusion criteria: The exclusion criteria of this study are as follows: (a) A history of schizophrenia or any other psychotic disorders; (b) Severe physical diseases (ie, cardiac and neurologic diseases, brain trauma, liver and kidney diseases, haematopoietic system and immune system dysfunction), or cancer, or other serious complicated diseases; (c) IQ < 70 is assessed by Wechsler Adult Intelligence Scale-Revised in China, or a specific of developmental delay or intellectual disability; (d) Abnormal laboratory test results with clinical significance which will affect the safety of participants as determined by the investigator; (e) A past and/or current abuse of alcohol, amphetamine or any other psychostimulants; (f) Suicidal ideation, plan, or suicidal behaviour in the last 3 months; (g) Clinically significant allergic reaction to broccoli; (h) Pregnancy or preparing for pregnancy, and/or lactation; (i) Participation in another clinical trial within the last 30 days. (j) Other conditions that make the candidate subject unsuitable for this study as determined by the principal investigators (eg, aggressive behaviour, safety concerns, difficulty to complete the follow-up, etc.).

The study will use the following exit/discontinuation criteria: (a) Voluntary discontinuation by the subject who is at any time free to discontinue his or her participation in the study, without prejudice to further assessment and treatment; (b) Severe non-compliance to protocol as judged by the investigator; (c) Subject meets criteria of transition to psychosis; (d) Subject meets exclusion criteria during the intervention (eg, physical diseases, pregnancy, etc.).

Interventions: A total of 300 CHR subjects will be randomly allocated to SFN group (n = 150) or placebo group (n = 150). The intervention duration with SFN or placebo is 52 consecutive weeks. SFN will be delivered as its precursor GR along with a conversion enzyme, myrosinase, which converts GR to SFN in the body. The dosage is six active tablets (411 μmol GR) per day. ZHIYINGUOSU, SFN-producing dietary supplement, is provided at no cost by Shenzhen Fushan Biotech Co., Ltd. (China). The placebo group will be given six placebo tablets per day. Active and placebo tablets are manufactured uniformly with same appearance and similar smell and taste by Shenzhen Fushan Biotech Co., Ltd. (China). Patient compliance will be assessed using Brief Adherence Rating Scale (BARS). The BARS is a brief, pencil-paper, clinician-administered adherence assessment instrument. It consists of four items: three questions and an overall visual analogue rating scale to assess the proportion of doses taken by the patient in the past month (Byerly, Nakonezny, & Rush, 2008). Tablets counting will be conducted monthly for the whole intervention period. After intervention, a 1-year follow-up will be conducted. Temporary use of antipsychotics or anti-depressants is allowed in the whole trial based on the recommendation of the treating clinician, and the information of specific drugs, dosage, treatment period and rationale will be recorded.

Safety: To evaluate the tolerability, we conducted a safety test in over 100 subjects, with the daily dosage is six active tablets. Apart from mild gastrointestinal discomfort, no significant safety or side-effect issues were found in this test.We also found that taking the tablets just after meal reduced the risk of gastrointestinal discomfort. Procedures in the proposed study allow the subject to increase the dosage gradually if the subject experiences significant gastrointestinal discomfort. If the subject experiences a serious adverse event his or her participation can be terminated.

Outcomes: Clinical investigators will collect general information such as gender, age, height, weight, body mass index, demographics and medical history. In addition, vital signs and laboratory tests results will be obtained. These will include body temperature, arterial pulse, blood pressure, heart rate, complete blood cell count, blood electrolytes (K, Na, Cl) and liver and kidney function tests.

The primary outcome is the 2-year conversion rate of psychosis at the end of follow-up (104 weeks). Psychosis conversion is operationally defined according to the criteria of POPS (presence of psychotic symptoms in SIPS/SOPS). Two are required: (a) at least one positive symptom is present at a psychotic level of intensity (rated at level '6' using SOPS); (b) any criterion symptom at sufficient frequency and duration or urgency: the symptom has occurred over a period of 1 month for at least 1 hour per day at a minimum average frequency of 4 days per week, or the symptom is seriously disorganizing or dangerous.

The secondary outcomes include: (a) the 1-year conversion rate of psychosis at the end of intervention period (52 weeks); (b) scores of SOPS; (c) scores of PANSS; (d) the duration of psychotic symptoms; (e) Global Assessment of Functioning; (f) individual predictive risk of psychosis calculated by NAPLS-2 psychosis risk calculator (Carrion et al., 2016) and SHARP psychosis risk calculator (Zhang et al., 2019); (g) scores of MATRICS consensus cognitive battery (MCCB) (Kern et al., 2008; Nuechterlein et al., 2008); (h) the number of participants who receive antipsychotic treatment during the trial; (i) levels of peripheral blood biomarkers of inflammation, oxidative stress and metabolism. Others: (a) Serious adverse events; (b) side-effects of SFN and placebo will be assessed by Systematic Assessment For Treatment Emergent Events (SAFTEE) scale (Levine & Schooler, 1986); (c) Compliance to SFN or placebo assessed using BARS; (d) Usage of antidepressants or other medications; (e) plasma and urinary measures of GR metabolites.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 45 Years

Eligibility

Inclusion Criteria:

1. Subjects meet the criteria of CHR according to the Structured Interview for Prodromal Syndromes (SIPS);

2. Subjects will have no history of being medicated with either antipsychotics or mood stabilizers at their first study visit;

3. Age, within the range of 15 to 45 years;

4. Patients and/or their legal guardians for those younger than 18 year old, can understand and sign informed consent, and agree to take the study interventions and complete all visits and examinations.

Exclusion Criteria:

1. A history of schizophrenia or any other psychotic disorders;

2. Severe physical diseases (ie, cardiac and neurologic diseases, brain trauma, liver and kidney diseases, haematopoietic system and immune system dysfunction), or cancer, or other serious complicated diseases;

3. IQ < 70 is assessed by Wechsler Adult Intelligence Scale-Revised in China, or a specific of developmental delay or intellectual disability;

4. Abnormal laboratory test results with clinical significance which will affect the safety of participants as determined by the investigator;

5. A past and/or current abuse of alcohol, amphetamine or any other psychostimulants;

6. Suicidal ideation, plan, or suicidal behaviour in the last 3 months;

7. Clinically significant allergic reaction to broccoli;

8. Pregnancy or preparing for pregnancy, and/or lactation;

9. Participation in another clinical trial within the last 30 days.

10. Other conditions that make the candidate subject unsuitable for this study as determined by the principal investigators (eg, aggressive behaviour, safety concerns, difficulty to complete the follow-up, etc.).

Related Conditions & MeSH terms

• Clinical High Risk Syndrome of Psychosis
• Mental Disorders
• Psychotic Disorders

Intervention

Dietary Supplement:
• Sulforaphane
Sulforaphane (SFN) is a natural compound extracts from cruciferous vegetables, especially broccoli, with cytoprotective, anti-inflammatory, and antioxidant effects.

Combination Product:
• Placebo
The placebo is safe, with no therapeutical effect, and has same appearance and similar smell and taste with active tablet.

Locations

Country	Name	City	State
China	Second Xiangya Hospital of Central South University	Changsha	Hunan
China	Guangzhou Psychiatric Hospital	Guangzhou	Guangdong
China	Shanghai Mental Health Center	Shanghai	Shanghai
China	Shanghai Pudong Nanhui Mental Health Center	Shanghai	Shanghai
China	Shanghai Xuhui District Mental Health Center	Shanghai	Shanghai
China	Shenzhen Kangning Hospital	Shenzhen	Shenzhen
China	Suzhou Psychiatric Hospital	Suzhou	Jiangsu
China	Tianjin Anding Hospital	Tianjin	Tianjin
China	the First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan

Sponsors (10)

Lead Sponsor	Collaborator
Shanghai Jiao Tong University School of Medicine	Guangzhou Psychiatric Hospital, Second Xiangya Hospital of Central South University, Shanghai Pudong Nanhui Mental Health Center, Shanghai Xuhui District Mental Health Center, Shenzhen Fushan Biotech Co., Ltd., Shenzhen Kangning Hospital, Suzhou Psychiatric Hospital, The First Affiliated Hospital of Zhengzhou University, Tianjin Anding Hospital

Country where clinical trial is conducted

China, 

References & Publications (12)

Addington J, Liu L, Buchy L, Cadenhead KS, Cannon TD, Cornblatt BA, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, Woods SW, Bearden CE, Mathalon DH, McGlashan TH. North American Prodrome Longitudinal Study (NAPLS 2): The Prodromal Symptoms. J Nerv Ment Dis. 2015 May;203(5):328-35. doi: 10.1097/NMD.0000000000000290. — View Citation

Bent S, Lawton B, Warren T, Widjaja F, Dang K, Fahey JW, Cornblatt B, Kinchen JM, Delucchi K, Hendren RL. Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Mol Autism. 2018 May 30;9:35. doi: 10.1186/s13229-018-0218-4. eCollection 2018. — View Citation

Carrion RE, Cornblatt BA, Burton CZ, Tso IF, Auther AM, Adelsheim S, Calkins R, Carter CS, Niendam T, Sale TG, Taylor SF, McFarlane WR. Personalized Prediction of Psychosis: External Validation of the NAPLS-2 Psychosis Risk Calculator With the EDIPPP Project. Am J Psychiatry. 2016 Oct 1;173(10):989-996. doi: 10.1176/appi.ajp.2016.15121565. Epub 2016 Jul 1. — View Citation

Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. doi: 10.1093/schbul/13.2.261. — View Citation

Kern RS, Nuechterlein KH, Green MF, Baade LE, Fenton WS, Gold JM, Keefe RS, Mesholam-Gately R, Mintz J, Seidman LJ, Stover E, Marder SR. The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization. Am J Psychiatry. 2008 Feb;165(2):214-20. doi: 10.1176/appi.ajp.2007.07010043. Epub 2008 Jan 2. — View Citation

Li H, Zhang T, Xu L, Tang Y, Cui H, Wei Y, Tang X, Woodberry KA, Shapiro DI, Li C, Seidman LJ, Wang J. A comparison of conversion rates, clinical profiles and predictors of outcomes in two independent samples of individuals at clinical high risk for psychosis in China. Schizophr Res. 2018 Jul;197:509-515. doi: 10.1016/j.schres.2017.11.029. Epub 2017 Dec 26. — View Citation

Li Z, Zhang T, Xu L, Wei Y, Tang Y, Hu Q, Liu X, Li X, Davis J, Smith R, Jin H, Wang J. Decreasing risk of psychosis by sulforaphane study protocol for a randomized, double-blind, placebo-controlled, clinical multi-centre trial. Early Interv Psychiatry. 2021 Jun;15(3):585-594. doi: 10.1111/eip.12988. Epub 2020 May 21. — View Citation

Miller TJ, McGlashan TH, Rosen JL, Cadenhead K, Cannon T, Ventura J, McFarlane W, Perkins DO, Pearlson GD, Woods SW. Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull. 2003;29(4):703-15. doi: 10.1093/oxfordjournals.schbul.a007040. Erratum In: Schizophr Bull. 2004;30(2):following 217. — View Citation

Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ 3rd, Gold JM, Goldberg T, Heaton RK, Keefe RS, Kraemer H, Mesholam-Gately R, Seidman LJ, Stover E, Weinberger DR, Young AS, Zalcman S, Marder SR. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008 Feb;165(2):203-13. doi: 10.1176/appi.ajp.2007.07010042. Epub 2008 Jan 2. — View Citation

Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, Zimmerman AW. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550-5. doi: 10.1073/pnas.1416940111. Epub 2014 Oct 13. — View Citation

World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. No abstract available. — View Citation

Zhang T, Xu L, Tang Y, Li H, Tang X, Cui H, Wei Y, Wang Y, Hu Q, Liu X, Li C, Lu Z, McCarley RW, Seidman LJ, Wang J; SHARP (ShangHai At Risk for Psychosis) Study Group. Prediction of psychosis in prodrome: development and validation of a simple, personalized risk calculator. Psychol Med. 2019 Sep;49(12):1990-1998. doi: 10.1017/S0033291718002738. Epub 2018 Sep 14. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serious adverse events	Serious adverse events	the whole process
Other	Side-effects of SFN and placebo	side-effects of SFN and placebo will be assessed by Systematic Assessment For Treatment Emergent Events (SAFTEE) scale	52 weeks
Other	Compliance	Compliance to SFN or placebo assessed using Brief Adherence Rating Scale	24 weeks
Other	Number of CHR subjects who use antidepressants or other medications	Usage of antidepressants or other medications	52 weeks
Other	Plasma and urinary measures of GR metabolites	Plasma and urinary measures of GR metabolites	24 weeks, 52 weeks, 104 weeks
Primary	2-year conversion rate of psychosis	The proportion of patients are diagnosed with psychosis in each group	104 weeks
Secondary	1-year conversion rate of psychosis	The proportion of patients is diagnosed with psychosis in each group	52 weeks
Secondary	Severity of prodromal symptoms	CHR subject's severity of prodromal symptoms is assessed according to the Scale of Prodromal Symptoms (SOPS) based on the SIPS interview	24 weeks, 52 weeks, 104 weeks
Secondary	Severity of psychotic symptom	CHR subject's severity of psychotic symptom is assessed according to the Positive and Negative Syndrome Scale (PANSS)	24 weeks, 52 weeks, 104 weeks
Secondary	Function	CHR subject's overall function is assessed by Global Assessment of Functioning(GAF)	24 weeks, 52 weeks, 104 weeks
Secondary	Predictive risk of psychosis	Predicted risk of psychosis by online psychosis risk calculator.	24 weeks, 52 weeks, 104 weeks
Secondary	Neurocognitive functioning	The MATRICS consensus cognitive battery (MCCB). Original version of the MCCB comprises 10 standardized cognitive measures for seven cognitive domains: speed of processing, attention/vigilance, working memory (verbal and nonverbal), verbal learning, visual learning, reasoning and problem solving, and social cognition. The 7 domain scores and a composite score were used as variables of neurocognition.Our group has previously contributed to the Chinese norms for the MCCB scores of tests. The kappa values for test-retest reliability of the subtests of the Chinese version ranges from 0.73 to 0.94.	24 weeks, 52 weeks, 104 weeks
Secondary	Level of inflammation in subjects' peripheral blood	Detecting expression levels of inflammation-related biomarkers in peripheral blood.	24 weeks, 52 weeks, 104 weeks
Secondary	Level of oxidative stress in subjects' peripheral blood	Detecting expression levels of oxidative stress-related biomarkers in peripheral blood.	24 weeks, 52 weeks, 104 weeks
Secondary	Level of metabolism in subjects' peripheral blood	Detecting expression levels of metabolism-related biomarkers in peripheral blood.	24 weeks, 52 weeks, 104 weeks