Treatment Study for Cognitive Deficits in Schizophrenia (TURNS)

• ClinicalTrials.gov Identifier: NCT00505076
• Recruitment Status: Completed
• First Posted: July 20, 2007
• Results First Posted: October 31, 2014
• Last Update Posted: October 31, 2014
• Sponsor: University of California, Los Angeles
• Collaborators: University of Maryland; Washington University School of Medicine; Massachusetts General Hospital; Nathan Kline Institute for Psychiatric Research; Columbia University; Duke University; Beth Israel Deaconess Medical Center
• Information provided by (Responsible Party): Stephen R. Marder, University of California, Los Angeles

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Schizophrenia
• Interventions: Drug: MK-0777; Drug: placebo
• Enrollment: 63

Participant Flow

Recruitment Details	Patients were recruited between June 2007 and July 2009.
Pre-assignment Details	46 subjects were excluded during screening.

Arm/Group Title	MK-0777 8 mg BID	MK-0777 3 mg BID	Placebo BID
Arm/Group Description	Subjects treated with MK-0777 GEM, 8 mg BID(twice daily)	Subjects treated with MK-0777 GEM, 3 mg BID (twice daily)	Subjects treated with 2 tablets placebo BID (twice daily)
Period Title: Overall Study
Started	22	19	22
Completed	19	17	17
Not Completed	3	2	5
Reason Not Completed
Adverse Event	1	0	1
Protocol Violation	2	1	2
Withdrawal by Subject	0	1	2

Baseline Characteristics

Arm/Group Title		MK-077 8 mg BID	MK-0777 3 mg BID	Placebo BID	Total
Arm/Group Description		Subjects treated with MK-0777 GEM, 8 mg BID(twice daily)	Subjects treated with MK-0777 GEM, 3 mg BID (twice daily)	Subjects treated with 2 tablets placebo BID (twice daily)	Total of all reporting groups
Overall Number of Baseline Participants		22	19	22	63
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	19 participants	22 participants	63 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	22 100.0%	19 100.0%	22 100.0%	63 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	22 participants	19 participants	22 participants	63 participants
		44.9 (8.7)	43.3 (9.3)	40.0 (10.9)	42.7 (9.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	19 participants	22 participants	63 participants
	Female	9 40.9%	8 42.1%	6 27.3%	23 36.5%
	Male	13 59.1%	11 57.9%	16 72.7%	40 63.5%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	22 participants	19 participants	22 participants	63 participants
		22	19	22	63

Outcome Measures

1. Primary Outcome

Title	Composite MATRICS Consensus Cognitive Battery Score
Description	The primary outcome measure is the composite score on the Matrics Consensus Cognitive Battery (MCCB). The MCCB composite score is a standardized mean of the seven domain scores. T-scores are standardized to normative data, and have an estimated mean of 50 and SD of 10 in the general healthy population. Data reduction for analysis of neurocognitive testing used the following steps: i) individual neurocognitive test scores at baseline and follow-up were converted to t-scores; ii) t-scores within the pre-specified cognitive domains measured by more than one test were averaged to obtain a domain-specific t-score; and iii) domain-specific t-scores were averaged to create the MCCB composite score.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Fifty-three participants completed the study: MK-0777 3mg BID: 18; MK-0777 8mg BID: 18; placebo: 17. Three participants dropped out prior to receiving study drug (one randomized to each group) and 1 participant dropped out prior to any post-randomization ratings (randomized to placebo). These participants were not included in analyses.

Arm/Group Title	MK-077 8 mg BID	MK-0777 3 mg BID	Placebo BID
Arm/Group Description:	Subjects treated with MK-0777, 8 mg BID	Subjects treated with MK-0777 , 3 mg BID	Subjects treated with placebo tablet BID
Overall Number of Participants Analyzed	18	18	17
Mean (Standard Deviation); Unit of Measure: composite score
	27.9 (12.7)	31.3 (13.9)	32.5 (14.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-077 8 mg BID, MK-0777 3 mg BID, Placebo BID
	Comments	An analysis of covariance (ANCOVA), adjusting for baseline scores, was used to compare treatment groups on cognitive and functional measures. The predefined primary cognition outcome measure was the MCCB (MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia Research) Consensus Cognitive Battery) composite T-score, tested at overall two-sided alpha=0.05.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.21
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

2. Secondary Outcome

Title	UPSA(UCSD Performance-Based Skills Assessment) Summary Score
Description	The UCSD Performance-Based Skills Assessment assessed functional capacity. The UPSA Summary Score has a range from 0 to 120. A higher score indicates less impairment.
Time Frame	Baseline and end of treatment, a total of four weeks.

Outcome Measure Data

Analysis Population Description

Fifty-three participants completed the study: MK-0777 3mg BID: 18; MK-0777 8mg BID: 18; placebo: 17. Three participants dropped out prior to receiving study drug (one randomized to each group) and 1 participant dropped out prior to any post-randomization ratings (randomized to placebo). These participants were not included in analyses.

Arm/Group Title	MK-077 8 mg BID	MK-0777 3 mg BID	Placebo BID
Arm/Group Description:	Subjects treated with MK-0777, 8 mg BID	Subjects treated with MK-0777 , 3 mg BID	Subjects treated with placebo tablet BID
Overall Number of Participants Analyzed	18	18	17
Mean (Standard Deviation); Unit of Measure: UPSA Summary Score
Baseline	91.7 (13.4)	85.0 (18.8)	95.0 (16.3)
End of Treatment	90.4 (12.8)	86.3 (18.7)	96.5 (15.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-077 8 mg BID, MK-0777 3 mg BID, Placebo BID
	Comments	The sample size was determined using the analysis of covariance power formula, n=2[za+zβ]2s2 (1-R2)/d2, with za=2.24, zβ=0.842 (corresponding to power=0.80), R=the correlation between baseline and end of study measures of the outcome, d the difference between groups, and s the standard deviation of the outcome. Actual recruitment was only about 20 participants per group, but the observed R≅0.9, suggesting power to detect an effect size of 0.49.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.47
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

3. Secondary Outcome

Title	Schizophrenia Cognition Rating Scale (SCoRS) Score
Description	The Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. The SCoRS Interviewer Global Rating of function has a range 1 to 10. Higher ratings indicate greater impairment.
Time Frame	4 Weeks (Baseline to End of Treatment)

Outcome Measure Data

Analysis Population Description

Fifty-three participants completed the study: MK-0777 3mg BID: 18; MK-0777 8mg BID: 18; placebo: 17. Three participants dropped out prior to receiving study drug (one randomized to each group) and 1 participant dropped out prior to any post-randomization ratings (randomized to placebo). These participants were not included in analyses.

Arm/Group Title	MK-077 8 mg BID	MK-0777 3 mg BID	Placebo BID
Arm/Group Description:	Subjects treated with MK-0777, 8 mg BID	Subjects treated with MK-0777 , 3 mg BID	Subjects treated with placebo tablet BID
Overall Number of Participants Analyzed	18	18	17
Mean (Standard Deviation); Unit of Measure: SCoRS Score
Baseline	4.1 (2.3)	4.8 (2.3)	3.8 (2.3)
End of Treatment	4.0 (2.4)	4.6 (2.1)	3.6 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-077 8 mg BID, MK-0777 3 mg BID, Placebo BID
	Comments	The sample size was determined using the analysis of covariance power formula, n=2[za+zβ]2s2 (1-R2)/d2, with za=2.24, zβ=0.842 (corresponding to power=0.80), R=the correlation between baseline and end of study measures of the outcome, d the difference between groups, and s the standard deviation of the outcome. Actual recruitment was only about 20 participants per group, but the observed R≅0.9, suggesting power to detect an effect size of 0.49.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.84
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	MK-077 8 mg BID		MK-0777 3 mg BID		Placebo BID
Arm/Group Description	Subjects treated with MK-0777 GEM, 8 mg BID(twice daily)		Subjects treated with MK-0777 GEM, 3 mg BID (twice daily)		Subjects treated with 2 tablets placebo BID (twice daily)
All-Cause Mortality
	MK-077 8 mg BID		MK-0777 3 mg BID		Placebo BID
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	MK-077 8 mg BID		MK-0777 3 mg BID		Placebo BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.76%)		1/18 (5.56%)		0/21 (0.00%)
Infections and infestations
Medical Hospitalization * [1]	0/21 (0.00%)	0	1/18 (5.56%)	1	0/21 (0.00%)	0
Nervous system disorders
Psychosis Hospitalization * [2]	1/21 (4.76%)	1	0/18 (0.00%)	0	0/21 (0.00%)	0
* Indicates events were collected by non-systematic assessment; [1] Fever with influenza; [2] Hospitalization for psychosis
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	3%
	MK-077 8 mg BID		MK-0777 3 mg BID		Placebo BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/21 (33.33%)		2/18 (11.11%)		5/21 (23.81%)
General disorders
Sedation *	2/21 (9.52%)	2	1/18 (5.56%)	1	1/21 (4.76%)	1
Dizziness *	2/21 (9.52%)	2	0/18 (0.00%)	0	1/21 (4.76%)	1
Fever *	2/21 (9.52%)	2	0/18 (0.00%)	0	0/21 (0.00%)	0
Headache *	1/21 (4.76%)	1	0/18 (0.00%)	0	2/21 (9.52%)	2
Musculoskeletal and connective tissue disorders
Limb pain *	0/21 (0.00%)	0	1/18 (5.56%)	1	1/21 (4.76%)	1
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Stephen R. Marder
• Organization: Semel Institute at UCLA
• Phone: 310-268-3647
• EMail: marder@ucla.edu

Publications:

Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995 Apr;52(4):258-66. doi: 10.1001/archpsyc.1995.03950160008002.

Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, Goldberg TE, Weinberger DR. Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex. 1999 Jan-Feb;9(1):20-6. doi: 10.1093/cercor/9.1.20.

Callicott JH, Ramsey NF, Tallent K, Bertolino A, Knable MB, Coppola R, Goldberg T, van Gelderen P, Mattay VS, Frank JA, Moonen CT, Weinberger DR. Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology. 1998 Mar;18(3):186-96. doi: 10.1016/S0893-133X(97)00096-1.

Carpenter WT Jr, Buchanan RW, Kirkpatrick B, Breier AF. Diazepam treatment of early signs of exacerbation in schizophrenia. Am J Psychiatry. 1999 Feb;156(2):299-303. doi: 10.1176/ajp.156.2.299.

Carter CS, Perlstein W, Ganguli R, Brar J, Mintun M, Cohen JD. Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry. 1998 Sep;155(9):1285-7. doi: 10.1176/ajp.155.9.1285.

Gold JM, Carpenter C, Randolph C, Goldberg TE, Weinberger DR. Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry. 1997 Feb;54(2):159-65. doi: 10.1001/archpsyc.1997.01830140071013.

Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996 Mar;153(3):321-30. doi: 10.1176/ajp.153.3.321.

Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004 Dec 15;72(1):41-51. doi: 10.1016/j.schres.2004.09.009.

Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000 Nov;57(11):1061-9. doi: 10.1001/archpsyc.57.11.1061. Erratum In: Arch Gen Psychiatry 2002 Jan;59(1):12. DiGiorgi Gerevini V [corrected to Di-Giorgi-Gerevini V].

Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003 Jul 16;23(15):6315-26. doi: 10.1523/JNEUROSCI.23-15-06315.2003.

Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005 Apr;6(4):312-24. doi: 10.1038/nrn1648.

McMahon RP, Arndt S, Conley RR. More powerful two-sample tests for differences in repeated measures of adverse effects in psychiatric trials when only some patients may be at risk. Stat Med. 2005 Jan 15;24(1):11-21. doi: 10.1002/sim.1837.

Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron. 2000 Oct;28(1):53-67. doi: 10.1016/s0896-6273(00)00085-4.

Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004 Dec 15;72(1):29-39. doi: 10.1016/j.schres.2004.09.007.

Park S, Holzman PS. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992 Dec;49(12):975-82. doi: 10.1001/archpsyc.1992.01820120063009.

Pierri JN, Chaudry AS, Woo TU, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry. 1999 Nov;156(11):1709-19. doi: 10.1176/ajp.156.11.1709.

Rao SG, Williams GV, Goldman-Rakic PS. Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. J Neurophysiol. 1999 Apr;81(4):1903-16. doi: 10.1152/jn.1999.81.4.1903.

Rao SG, Williams GV, Goldman-Rakic PS. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory. J Neurosci. 2000 Jan 1;20(1):485-94. doi: 10.1523/JNEUROSCI.20-01-00485.2000.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Georgiades A, Davis VG, Atkins AS, Khan A, Walker TW, Loebel A, Haig G, Hilt DC, Dunayevich E, Umbricht D, Sand M, Keefe RSE. Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients. Schizophr Res. 2017 Dec;190:172-179. doi: 10.1016/j.schres.2017.03.040. Epub 2017 Apr 20.

Buchanan RW, Keefe RS, Lieberman JA, Barch DM, Csernansky JG, Goff DC, Gold JM, Green MF, Jarskog LF, Javitt DC, Kimhy D, Kraus MS, McEvoy JP, Mesholam-Gately RI, Seidman LJ, Ball MP, McMahon RP, Kern RS, Robinson J, Marder SR. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry. 2011 Mar 1;69(5):442-9. doi: 10.1016/j.biopsych.2010.09.052. Epub 2010 Dec 8.

• Responsible Party: Stephen R. Marder, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00505076
• Other Study ID Numbers: TURNS02; HHSN278200441003C ( Other Grant/Funding Number: NIMH grant )
• First Submitted: July 19, 2007
• First Posted: July 20, 2007
• Results First Submitted: April 27, 2011
• Results First Posted: October 31, 2014
• Last Update Posted: October 31, 2014